Background: Diabetic wounds remain difficult to treat due to persistent oxidative stress, chronic inflammation, and vascular dysfunction. These factors reinforce each other, forming a vicious cycle that leads to delayed healing, poor angiogenesis, and high amputation risk. Existing therapies often fail because they are unable to address these challenges simultaneously. Therefore, this study aimed to develop a hybrid extracellular vesicle system that targets these multiple barriers concurrently to promote diabetic wound healing. Methods: A biohybrid nanovesicle system (DFO@HEVs) was built by fusing endothelial cell-derived extracellular vesicles with neutrophil-derived nanovesicles (forming hybrid extracellular vesicles, HEVs), which were loaded with deferoxamine (DFO). The vesicles were tested for their physicochemical properties, drug loading, and safety. Therapeutic effects were studied in vitro using HG/PA-stimulated endothelial cells and macrophages and in vivo in diabetic mouse wounds. The analyses included microscopy, flow cytometry, histology, transcriptomics, and database-based single-cell RNA sequencing. Results: DFO@HEVs showed dual targeting: homing to endothelial cells via CXCR4 and to inflamed sites via β2 integrin. They enhanced endothelial uptake, promoted angiogenesis through PI3K/AKT/HIF-1 α and VEGF signaling pathways, and reduced oxidative stress and ferroptosis by activating Nrf2 and upregulating antioxidant genes. They also shifted macrophages toward an anti-inflammatory M2 phenotype, boosted efferocytosis, and suppressed NF-κB/NLRP3-driven inflammation. In diabetic mice, treatment with DFO@HEVs accelerated wound closure, re-epithelialization, collagen deposition, and new vessel formation, while lowering neutrophil infiltration, reactive oxygen species levels, ferroptosis, and pro-inflammatory cytokines, creating a healing-supportive environment. Conclusions: DFO@HEVs provided a hybrid nanovesicle system for combined membrane and drug delivery. By promoting angiogenesis, limiting ferroptosis, and resolving inflammation, they disrupted the cycle that prevented diabetic wound repair. This approach shows a strong potential as a new treatment for chronic wounds.

Background: Hypertrophic scarring remains a critical challenge in regenerative medicine because of the limited efficacy of current antifibrotic therapies. Although dermal papilla cells (DPCs) exhibit intrinsic scar-inhibitory potential, their therapeutic utility is constrained by rapid replicative senescence and poor scalability in traditional monolayer cultures, necessitating innovative strategies to enhance cellular functionality and manufacturing feasibility. Methods: A self-feeder layer 3D (SFL-3D) platform was established to reprogram primary human DPCs into rejuvenated three-dimensional DPC (tdDPC) spheroids via autocrine–paracrine signalling activation. tdDPC-derived extracellular vesicles (tdDPC-EVs) were isolated from culture supernatants by differential centrifugation. The antifibrotic effects of tdDPC-EVs were systematically evaluated using human scar fibroblasts through scratch wound healing assays, CCK-8 proliferation assays, and fibrotic marker analysis [Western blotting and immunofluorescence staining for α-smooth muscle actin (α-SMA) and collagen I]. Bioinformatics was used to predict key pathways involved in hypertrophic scar (HS) pathogenesis, whereas gain/loss-of-function studies investigated the miR-26a-5p/CCNE2 regulatory axis. Therapeutic validation was performed in a rabbit ear hypertrophic scar model with histopathological and molecular profiling. Results: Compared with conventional 3D cultures, the SFL-3D system demonstrated superior proliferative support, enabling stable tdDPC expansion beyond 10 passages while maintaining high viability and enhanced EV biogenesis. miR-26a-5p-enriched tdDPC-EVs attenuated fibrosis through two mechanisms: (1) silencing CCNE2 to block PI3K/AKT-driven collagen overproduction and (2) suppressing α-SMA+ myofibroblast differentiation. In the rabbit ear HS model, tdDPC-EV administration reduced the scar elevation index and restored the collagen I/III ratio to near-physiological levels. Conclusions: This study positions tdDPC-EVs as a scalable acellular therapy that overcomes the replicative senescence and manufacturing limitations of cellular approaches. The antiscarring efficacy of these EVs, which is mediated by the miR-26a-5p/CCNE2/PI3K/AKT axis, highlights their clinical potential as precision-targeted strategies for hypertrophic scar management. The SFL-3D platform further provides a translatable framework for EV-based regenerative therapeutics.

Chronic diabetic wounds pose a serious health and economic burden globally. In recent years, there has been widespread attention on the research of functional and even personalized wound dressings, among which responsive smart nanofiber dressings made using electrospinning technology have shown great potential. Nanofibers have advantages such as extremely fine pore size, high porosity, and large specific surface area. By combining electrospinning technology with responsive materials and integrating electronic engineering and other manufacturing techniques, it is possible to weave smart nanofibers that can respond to specific diabetic wound environments (such as low pH, high reactive oxygen species, high glucose concentration, and overexpressed enzymes) or external conditions (such as temperature, light, and magnetic fields). This allows for the monitoring of the wound microenvironment and/or the automatic release of drugs based on changes in the wound microenvironment. Compared with ordinary dressings, this dressing can not only predict the wound state, but also respond to the specific wound (such as diabetic wound) microenvironment to promote wound healing rapidly and accurately. This article outlines the characteristics of the chronic diabetic wound microenvironment, electrospinning technology, and its application in responding to the chronic diabetic wound microenvironment.

Background: Burns and wounds cause significant physical and psychological distress, with pain being a major barrier to recovery. Traditional pharmacological methods for pain management carry risks such as side effects and dependency. Virtual reality has emerged as a non-invasive, distraction-based technique that may reduce pain perception during wound care by modulating sensory input. Methods: This systematic review and meta-analysis, conducted following PRISMA guidelines and registered in PROSPERO (CRD420251005004), assessed the effectiveness of virtual reality in managing pain during wound and burn care. A comprehensive search of PubMed, Web of Science, Scopus, and Cochrane Library was conducted in March 2025. Eligible studies included randomized controlled trials comparing virtual reality interventions to standard care or other distraction techniques in patients with active wounds or burns. Data on pain outcomes, as well as physiological indicators, were extracted. Meta-analysis was performed using a random-effects model and Hedges’ g as the effect size estimator. The analysis was performed with SPSS version 29 and the risk of bias was assessed using the RoB 2.0 tool. Results: Eleven studies (n = 936 participants) were included, with diverse wound types (burns, surgical, limb injuries) and virtual reality setups, predominantly immersive. The overall pooled effect showed a statistically significant reduction in pain using virtual reality (g = −1.528; 95% CI: −2.259 to −0.797; p < 0.001), indicating a moderate-to-large effect. Subgroup analysis revealed that virtual reality was most effective in children (g = −2.348), followed by adolescents (g = −0.538), while adults showed a non-significant effect (g = −1.453). High heterogeneity (I² = 95.5%) was explained by age group differences and sensitivity analysis. No significant publication bias was detected. Conclusions: Virtual reality appears to be a promising tool for reducing procedural pain, particularly in children with wounds or burns. Its efficacy in adolescents is moderate, while evidence in adults remains inconclusive. Given its non-pharmacological nature and potential to improve patient experience, virtual reality warrants broader implementation and further age-specific research in wound care settings.

Background: Following spinal cord injury (SCI), mechanical trauma and an inflammatory microenvironment activate the PKC δ-TRPA1 pathway, resulting in calcium overload within neurons and subsequently inducing endoplasmic reticulum (ER) stress–mediated neuronal apoptosis. The mechanisms and therapeutic potential of electroacupuncture (EA) in the treatment of SCI have yet to be fully elucidated. This study aimed to explore the causes of neuronal Ca²⁺ overload post-SCI and to investigate the neuroprotective and regenerative mechanisms of EA in an SCI mouse model. Methods: C57BL6 mice were randomly divided into a Sham group, an SCI group, and an SCI + EA group. The Basso Mouse Scale, motor-evoked potential, and movement videos of the mice were captured, and DeepLabCut was used to analyze the recovery of motor function. Western blotting was used to detect the protein levels of related indicators. Immunofluorescence staining was used to analyse the cellular localization and fluorescence intensity of each indicator. Hematoxylin and eosin staining and Nissl staining were used for histological evaluation. EA treatment resulted in higher BMS scores; increased ankle, knee, and hip mobility; and improved hindlimb support in the EA group. Results: PKC δ and TRPA1 protein expression was upregulated after SCI, and neuronal calcium ion overload occurred, leading to neuronal ER stress–induced apoptosis. After EA treatment, inflammatory microenvironment-related indicators were downregulated, which inhibited the activation of calcium channels by PKC δ-TRPA1, reduced ER stress–induced apoptosis caused by calcium overload in neurons, and protected neurons from secondary injury. EA increases the expression of neurotrophic factors and promotes nerve regeneration, and we found that EA treatment promotes axonal elongation by stabilizing microtubules. Conclusions: According to our findings, (i) mechanical injury and the inflammatory microenvironment after SCI activate PKC δ-TRPA1, which is important for neuronal ER stress and apoptosis caused by neuronal calcium overload. (ii) EA treatment reduces the expression of PKC δ-TRPA1 as well as the ER stress and apoptosis caused by neuronal calcium overload. (iii) EA promoted neurogenesis and axonal regeneration by promoting the secretion of neurotrophic factors and promoted axon elongation by stabilizing microtubules, thus promoting the recovery of motor function in SCI mice.

The lymphatic system serves many more functions than simply maintaining tissue fluid homeostasis, and its structural and functional changes indicate the occurrence of disease. Current clinical methods for the assessment of the lymphatic system, however, are severely limited because of their nontargeting ability, invasiveness, high cost, and radiation risk. Herein, we propose a simple and painless method for visualizing and quantifying the lymphatic system. This method is based on the noninvasive administration of a novel lymphatic tracer via dissolvable microneedles, followed by the application of a portable detection device for near-infrared (NIR) imaging. The tracer is prepared by incorporating the clinically approved NIR fluorescent dye methylene blue (ME) into the nanomaterial monomethoxyl poly(ethylene glycol)-b-poly(ε-caprolactone) (MPEG-PCL@ME). This novel tracer displays superior fluorescence properties, stability, biocompatibility, and targeting features in comparison with ME solution alone. Lymphography with MPEG-PCL@ME in vivo clearly revealed the lymphatic vessel morphology. Notably, compared with ME and indocyanine green, MPEG-PCL@ME can easily identify the dominant lymphatic vessels and nodes in rats with higher imaging quality. Furthermore, a series of segmental contracting sections are detected with MPEG-PCL@ME, allowing straightforward identification of the lymphatic pump, which provides direct evidence for exquisitely evaluating lymphatic functions.

Research shows that the microbiome of the skin is present as an active contributor to wound healing processes by moving past its historical infection-related function. The review investigates how commensal and probiotic bacteria affect immunomodulation while accelerating epithelial growth, together with tissue repair processes. Researchers use modern methods to link immunological concepts with material science along with synthetic biological techniques to study engineered probiotics which transform current wound treatments. The research study represents an extensive integration of recent findings concerning probiotic-mediated immunomodulatory operations and engineered approaches that improve probiotic delivery systems and their performance during skin wound healing procedures. Recent genetically engineered Lactobacillus reuteri strains that express chemokines like CXCL12 have been found to promote wound healing to an accelerated rate in animal models, and pre-clinical phases of clinical trials in the setting of diabetic foot ulcers (DFU) has demonstrated safety and therapeutic potential. Simultaneously, another live biotherapeutic product has been validated in terms of regenerative and immunomodulatory properties in animal models and in a clinical trial, a multi-cytokine-integrated strain of Lactococcus cremoris secreting FGF-2, IL-4, and CSF-1 promoted faster wound healing in diabetic mice and healed 83% of subjects in a Phase I DFU study. The range of probiotic therapies for trauma care expands due to advancements in probiotic delivery using materials and membrane vesicles derived from probiotics. This review builds a detailed framework that connects core immune functions with modern engineering methods for developing smart wound healing systems that combine engineered probiotics with bioresponsive materials and real-time monitoring systems. Engineered probiotics promise to become an alternative strategy for treating chronic wounds and infection-related complications that currently create significant medical problems.

Background: The expression of CX3CR1 is regulated by the gut microbiota and is correlated with the prognosis of sepsis in patients. However, the underlying mechanism has remained uncertain. This study aims to explore the role of gut microbiota components in regulating CX3CR1 expression and its impact on pneumonia-induced lung injury during sepsis. Methods: Mice were fed a mixture of antibiotics to establish a pseudogerm-free mouse model and then infected with Klebsiella pneumoniae. Fecal microbiota transplantation (FMT) was performed on microbiota-depleted mice, and 16S rRNA gene sequencing and targeted metabolomics were used to identify the key metabolites. Flow cytometry was employed to analyze the phenotypes of natural killer (NK) cells. Butyric acid was added as a supplement for rescue. Next, NK92 cells were pretreated with butyric acid to explore the potential signaling pathways involved. Results: In the animal study, we revealed that the expression of CX3CR1 on NK cells depended on the intestinal microbiota and its metabolites, which were related to the survival rates of gut microbiota-depleted mice after K. pneumoniae infection. FMT increased the percentage of CX3CR1+ NK cells in the lungs of these mice, restored the disordered microbiota and metabolites, and alleviated the lung injury induced by infection. Among the metabolites, butyric acid was identified as the key metabolite and was shown to increase the proportion of CX3CR1+ NK cells and interferon (IFN)-γ secretion, reduce bacterial loads, increase lung tissue damage, and increase survival rates. In vitro, butyric acid activated the PI3K/AKT pathway in NK92 cells, promoted CX3CR1 expression, and enhanced NK cell activity and migration ability. Conclusions: We concluded that butyric acid alleviated K. pneumoniae-induced lung injury by regulating CX3CR1+ NK cells via the PI3K/AKT pathway.

Sepsis-associated encephalopathy (SAE) is a secondary cerebral dysfunction of the central nervous system (CNS) caused by sepsis and is associated with high mortality rate and poor prognosis. It significantly affects the quality of life of survivors. The pathological mechanisms associated with SAE include dysfunction of the blood–brain barrier (BBB), activation of glial cells, ischemic injury, leukocyte transmigration, and disturbances in neurotransmitters. The mechanisms of SAE interact with and contribute to its development. Numerous studies have demonstrated that the intestinal microbiota affects not only the health of the gut but also that of other organs. Throughout the progression of SAE, alterations in the gut microbiome composition lead to the production of toxic substances that damage the intestinal barrier and enter the bloodstream. This damage negatively affects BBB permeability and initiates a cascade of neuroinflammatory responses that result in neuronal injury. Conversely, specific microbiome-derived derivatives play exhibit a neuroprotective role in regulating brain function. Therefore, gut–brain crosstalk may be a crucial factor in brain dysfunction. This paper reviews the relationship between the intestinal microbiota and SAE, aiming to explore the role of the intestinal microbiota in SAE and potential therapeutic targets.

Burn injury remains a major global health challenge, causing an estimated 180 000 deaths annually. The marked heterogeneity in burn severity, complications, and outcomes highlights the need for more objective and efficient evaluation strategies. Artificial intelligence (AI) has emerged as a promising approach to support clinical decision-making and improve patient care in this field. In this narrative review, we summarize the growing applications of AI in burn care, including the assessment of burn depth and total body surface area, monitoring of wound healing, prediction of postburn complications, and estimation of clinical outcomes. AI-based models have demonstrated strong performance in automating wound assessment, optimizing fluid resuscitation, and predicting complications such as sepsis, inhalation injury, and acute kidney injury. Furthermore, AI-driven prediction of mortality risk and hospital length of stay has shown potential to inform early interventions and improve resource allocation. Despite encouraging progress, most studies to date rely on small, single-center datasets and limited model validation, underscoring the need for larger, multi-institutional efforts, and standardized data sharing. Integrating AI into burn management holds great promise for enhancing diagnostic precision, forecasting outcomes, and personalizing treatment strategies. As these technologies advance, clinician familiarity and collaboration with AI tools will be critical to fully realize their potential in transforming burn care.

Background: Infectious bone defects are characterized by persistent bacterial invasion and an immune microenvironment imbalance, which significantly hinders bone regeneration. Recently, numerous bone repair materials have been developed to address the complex pathological microenvironment associated with infectious bone defects. However, dynamic changes in the defect size after infectious debridement pose a significant challenge for achieving effective bone integration of artificial bone grafts. Therefore, there is a need to develop an integrated scaffold with antibacterial, immunomodulatory, and osteogenic properties to achieve filling of irregular bone defects. Methods: Using low-temperature printing combined with the freeze-drying technology, a shape-memory scaffold with a biomimetic porous structure of cancellous bones was fabricated by compositing left-handed poly(L-lactic acid)-trimethylene carbonate (PLLA-TMC) with citric acid-modified hydroxyapatite (CHA). The scaffold (PT/CHA) was further coated with a metal-polyphenol network tannic acid-magnesium (TA-Mg) on its surface through the “mussel” effect, enabling the sequential treatment of infectious bone defects. Results: The scaffold can adaptively integrate with defect interfaces at the physiological temperature (37°C), achieving superior bone integration performance. The incorporation of citric-acid-modified hydroxyapatite effectively optimizes the polymer-inorganic phase printing ink system, significantly enhancing the mechanical strength and mineralization capacity of the scaffold. Meanwhile, the external tannic-acid-magnesium metal-polyphenol coating (TA-Mg) demonstrates excellent pathogen clearance properties both in vitro and in vivo. It also influences macrophage polarization to regulate the immune microenvironment, ultimately promoting bone regeneration in infectious bone defects. Conclusions: The PT/CHA@TA-Mg scaffold achieves bone integration through adaptive filling and enables the multi-stage treatment of infectious bone defects via antibacterial, immune-regulatory, and osteogenic differentiation.

Background: The accumulation of intracellular glycolytic lactate is a hallmark characteristic of chondrocytes. Histone lactylation, a post-translational modification mediated by lactate, plays a pivotal role in regulating the physiological functions of chondrocytes and contributes to the pathogenesis of posttraumatic osteoarthritis. This study was designed to investigate the role of glycolytic lactate-dependent histone H3 lysine 56 lactylation (H3K56la) in modulating the synthesis of type II collagen in chondrocytes. Furthermore, through a combination of laboratory-based and animal experimental approaches, the study sought to uncover new insights into potential therapeutic strategies for the management of posttraumatic osteoarthritis. Methods: In in vitro experiments, the researchers first conducted assays to inhibit and induce histone lactylation in chondrocytes, subsequently measuring changes in the expression levels of hypoxia-inducible factor 1 alpha (HIF 1 α) and the type II collagen alpha 1 chain gene (Col2a1). Next, we assessed alterations in intracellular lactylation levels and Col2a1 expression following either knockdown or overexpression of HIF 1 α in chondrocytes. To further elucidate the regulatory relationship between HIF 1 α and Col2a1, chromatin immunoprecipitation assays were performed to investigate the transcriptional control exerted by HIF 1 α on the Col2a1 gene promoter. In addition, murine models of posttraumatic osteoarthritis were developed using anterior cruciate ligament transection surgery. Both in vivo and in vitro experiments were then carried out to explore the chondroprotective mechanisms and therapeutic potential associated with modulation of histone lactylation in chondrocytes. Results: Induction of histone lactylation in chondrocytes led to a significant upregulation of HIF 1 α expression. Conversely, knockdown of HIF 1 α resulted in a marked reduction in both H3K56 lactylation and Col2a1 expression. It was found that H3K56la and HIF 1 α functioned synergistically to positively regulate collagen synthesis, with HIF 1 α directly binding to the promoter region of the Col2a1 gene to enhance its transcription. Treatment with α-ketoglutarate modified the cellular redox state and contributed to increased expression of both H3K56la and Col2a1. Conclusions: The glycolytic lactate/H3K56la/HIF 1 α regulatory axis plays a positive regulatory role in the synthesis of type II collagen in chondrocytes by facilitating the binding of HIF 1 α to the Col2a1 gene promoter. Activation of this molecular pathway holds promise as a novel therapeutic strategy for the treatment of posttraumatic osteoarthritis.

Trauma represents a significant global health issue, often resulting in devastating and long-lasting effects on the body throughout a patient’s life. Organ inflammation and dysfunction caused by trauma present additional challenges for clinicians. Therefore, understanding the cellular and molecular mechanisms of post-trauma systemic inflammation and organ dysfunction is essential for improving the management of trauma. This review aims to summarize current updates on the findings that explore different mechanisms of trauma-induced inflammation and organ dysfunction, highlighting the recent understanding of the vital roles of damage-associated molecular patterns, trauma-induced cell death, organ–organ cross-talk pathways, and the gut microbiota in the development and progression of post-traumatic systemic inflammation. We also discuss new approaches that can potentially guide further investigations of trauma diagnosis, treatment, and prognosis.

Background: Diabetic wound healing is often impaired due to the high-glucose microenvironment in patients. Among the relevant factors, bacterial infection and overproduction of reactive oxygen species (ROS) have critical roles, and sustained oxidative stress further impairs angiogenesis and increases apoptosis, thereby hindering wound repair. To reduce these effects, we aimed to develop an injectable temperature-sensitive cellulose hydrogel exhibiting anti-apoptotic, oxidative stress-attenuating, antimicrobial, and multi-species enzymatic activities. Methods: By simulating the dual active sites of natural copper–zinc superoxide dismutase (CuZn–SOD), a bimetallic mimetic nanoenzyme [Cu/Zn-metal–organic framework (MOF)] was synthesized. Subsequently, Cu/Zn-MOF was incorporated into a hydroxypropyl methylcellulose hydrogel, and the gelation temperature was adjusted to enable a sol-to-gel transition near physiological temperature. A rheometer was used to measure the gelation temperature, and scanning electron microscopy was performed to characterize the surface morphology. The hydrogels were evaluated for multiple enzyme-like activities, including those of SOD, glutathione peroxidase (GPx), thiol peroxidase (TPx), and ascorbate peroxidase (APx). Mouse fibroblasts (L929 cells) and human umbilical vein endothelial cells were used to assess antioxidant, pro-migratory, pro-angiogenic, and anti-apoptotic properties. Antimicrobial activity was assessed against Escherichia coli and Staphylococcus aureus. Western blotting was performed to verify potential anti-inflammatory mechanisms. Finally, wound and infected-wound models were established in diabetic mice to evaluate the hydrogel’s effects on wound repair. Results: The hydrogel exhibited a sol-to-gel transition at 37°C and demonstrated favorable injectability and hydrophilicity, providing a moist healing environment. The Cu/Zn-MOF nanoenzymes demonstrated four enzyme-like activities (SOD, GPx, TPx, and APx), enabling cascade ROS scavenging, which was further confirmed in cellular experiments. The Cu/Zn-MOF nanoenzymes also modulated Sirt1/nuclear factor-κ beta expression to influence inflammatory factor release, thereby exhibiting strong anti-inflammatory activity. The hydrogel also exerted cell migration, angiogenesis, and anti-apoptotic effects. Antimicrobial assays showed kill rates of 99.39% and 99.67% against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), respectively. In a diabetic mouse wound model, the hydrogel significantly enhanced pro-healing effects by promoting neovascularization and collagen deposition through ROS and bacterial clearance, thereby reducing the inflammatory response. Conclusions: Biomimetic nanoenzymes were synthesized and incorporated into temperature-sensitive injectable hydrogels, which exhibited strong antioxidant and antimicrobial activities that have considerable potential for diabetic wound therapy.

Background: Sepsis is a life-threatening condition characterized by profound immune dysregulation and organ dysfunction. The functional impairment of dendritic cells (DCs) in septic patients is well-documented and contributes significantly to sepsis-induced immunosuppression; yet the underlying mechanisms remain poorly understood. Tripartite motif 13 (TRIM13) has been identified as an immune regulator with predominantly suppressive effects. Here, we aimed to investigate the potential role of TRIM13 restriction in promoting the DC-mediated immune response during sepsis. Methods: Splenic DCs were isolated from wild-type (WT) and DC-specific Trim13 conditional knockout (Trim13 cKO) mice post-cecum ligation and puncture (CLP). These cells were subsequently analyzed by proteomics, immunoblotting, flow cytometry, and transmission electron microscopy (TEM). DC2.4 cells were infected with either Trim13 shRNA or a Trim13 overexpression lentiviral vector and treated with different pharmacological inhibitors. Protein interactions were examined via coimmunoprecipitation (Co-IP) and confocal microscopy. Cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA), and organ lesions were assessed through hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC) for CD45, and TUNEL assays. Results: TRIM13 expression was rapidly upregulated in DCs following septic challenge. Deletion of TRIM13 in DCs disrupted the endoplasmic reticulum (ER)-associated degradation (ERAD) and ER-selective autophagy (ER-phagy)-mediated degradation of the stimulator of interferon genes (STING), leading to sustained STING activation and enhanced DC function. STING signaling promoted the p-IRF3 nuclear translocation, NLRP3 inflammasome priming, and transient DC pyroptosis, thereby exacerbating hyperinflammation in the acute phase of sepsis. Over the longer term, prolonged STING signaling inhibited DCs from adopting the immunosuppressive phenotype and promoting the DC-mediated immune response. Ultimately, TRIM13 deficiency in DCs ameliorated sepsis-induced immunosuppression, preserved organ function in the late phase of sepsis, and reduced overall mortality in septic mice. Conclusions: TRIM13 acts as a key negative regulator of DC function during sepsis. Restricting TRIM13 sustains DC immunostimulatory property, counteracts sepsis-induced immunosuppression, and improves survival outcomes. These findings highlight TRIM13 as a potential therapeutic target for sepsis management.

Tendon–bone interface injuries, such as rotator cuff tears and anterior cruciate ligament ruptures, remain challenging due to the enthesis’s complex structure and poor healing capacity. Conventional repair often fails to restore the fibrocartilaginous transition, causing mismatched integration and high retear rates. Biomaterial-based scaffolds provide biomechanical support and bioactive regulation, showing great promise for regeneration. Recent advances span natural polymers, synthetic polymers, bioceramics, and composites, with designs evolving from monophasic to multiphasic, gradient-based, and functionalized scaffolds. Emerging strategies emphasize immunomodulation, bio-signal delivery, and physical responsiveness, establishing a structure–signal–function paradigm to guide multi-tissue integration. However, translation faces major barriers, including inadequate animal models, manufacturing and scalability challenges, long-term safety concerns, and regulatory complexity, as well as the need to balance personalization with cost. Future directions point to intelligent biomaterials, AI-driven design, and integrated translational frameworks to bridge preclinical research and clinical application. Overall, advanced scaffold engineering offers transformative potential for functional tendon–bone regeneration, but successful translation will depend on close collaboration among biology, materials science, engineering, and medicine.

Background: PANoptosis is a comprehensive form of cell death regulation that involves the interplay of pyroptosis, apoptosis, and necrosis. As a key regulator of PANoptosis, TAK1 plays a crucial role in multiple cell death pathways. However, its specific mechanism in the process of diabetic wound (DW) healing remains unclear. This study aimed to explore the role of TAK1 in regulating PANoptosis and its impact on DW healing. Methods: We used immunofluorescence, TUNEL staining, and EthD-III staining to analyse the relationship between TAK1 activity and PANoptosis. RNA sequencing was used to investigate the regulatory role of TAK1 and the NF-κB pathway under high-glucose conditions. Additionally, molecular docking and coimmunoprecipitation experiments were performed to verify the interaction between TAK1 and p65. Finally, a mouse model was used to study the effects of TAK1 knockdown on wound healing. Results: Our findings revealed that PANoptosis is significantly present in DW, with markedly upregulated TAK1 expression under high-glucose conditions. The inhibition of TAK1 expression significantly reduced cell death and promoted cell proliferation and migration. Mechanistically, TAK1 interacts with p65 through the NF-κB pathway, activating downstream signals that exacerbate cell damage in a high-glucose environment. TAK1 knockdown significantly suppressed PANoptosis, promoted microvascular and collagen formation, reduced inflammation, and further accelerated wound healing. Conclusion: TAK1 regulates PANoptosis by activating the NF-κB signalling pathway, thereby playing a crucial role in DW healing. Inhibiting TAK1 may represent a potential strategy to improve wound healing, with significant potential for clinical application.

Background: The spatiotemporal regulation of inflammatory dynamics is critical for successful wound healing. However, the precise mechanistic role of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in orchestrating these processes remains incompletely characterized. This study aimed to delineate the specific mechanisms by which NLRP3 governs cellular and molecular events during wound healing. Methods: Multi-omics sequencing data were utilized to profile NLRP3 inflammasome activation dynamics in murine and human acute wound models. Nlrp3^−/− mice were generated using CRISPR-Cas9 technology. In vitro and in vivo functional assays were performed to assess NLRP3-dependent regulation of macrophage and fibroblast recruitment, polarization, and phenotype modulation. Results: NLRP3ispredominantlyexpressedinmacrophagesandneutrophilsduringtheinflammatoryphaseofwoundhealing. Global deletion of Nlrp3 reduces IL-1 β, the main downstream effector, attenuates CCL/CXCL chemokine signaling, decreases both inflammatory and pro-reparative cell infiltration, and disrupts the phenotypic switching of macrophages and fibroblasts, collectively delaying wound closure. However, the resulting low-inflammatory microenvironment in Nlrp3^−/− mice may upregulate Wnt and Notch signaling early in the repair phase, curbing fibrosis and promoting appendage regeneration. Partial IL-1 β blockade in WT mice recapitulates the NLRP3-null phenotype, whereas IL-1 β reconstitution in knockout mice accelerates healing but increases fibrosis. Moreover, the NLRP3 protein also modulates fibroblast phenotype independently of inflammasome activation via a ROS-dependent mechanism. Conclusion: NLRP3 exerts dual-phase regulatory roles in wound healing: (i) during inflammation, it drives chemokine- mediated macrophage/fibroblast recruitment and M1 polarization while suppressing fibroblast-mediated repair via IL-1 β signaling; (ii) later, NLRP3 deficiency enhances Wnt/Notch signaling, promoting structural restoration despite transiently delayed healing. Moreover, fibroblasts with high NLRP3 expression engage an inflammasome-independent NLRP3/ROS axis that augments activation of TGF- β/Smad signaling. These findings position NLRP3 as a potential therapeutic target for modulating phase-specific inflammatory and regenerative responses.

Background: Persistent oxidative stress and aberrant inflammatory responses are major contributors to delayed wound healing in diabetic patients. Endothelial cell pyroptosis, a form of inflammatory programmed cell death, plays a critical role in vascular dysfunction and impaired tissue regeneration in diabetic wounds. Targeting endothelial pyroptosis therefore represents a promising therapeutic strategy. This study aims to develop a multifunctional nanofibrous scaffold capable of suppressing oxidative stress-induced endothelial pyroptosis while modulating the inflammatory microenvironment to promote angiogenesis and diabetic wound repair. Methods: In this study, a pH-responsive nanoplatform based on zinc–imidazolate metal–organic frameworks (ZIF-8) was constructed for the controlled delivery of luteolin (Lut), a natural flavonoid with anti-inflammatory and antioxidant properties. The physicochemical characteristics, drug-loading efficiency, and pH-responsive release behavior of Lut@ZIF-8 nanoparticles were systematically evaluated. The effects of Lut@ZIF-8 on oxidative stress, endothelial pyroptosis, and angiogenic function were investigated in vitro, while therapeutic efficacy was further assessed in a diabetic mouse wound model using Lut@ZIF-8-loaded fibrous scaffolds. Results: Lut@ZIF-8 nanoparticles exhibited uniform morphology, high drug-loading efficiency, and sustained drug release under mildly acidic conditions mimicking the diabetic wound microenvironment. In vitro, Lut@ZIF-8 effectively suppressed reactive oxygen species accumulation and inhibited endothelial cell pyroptosis by downregulating the activation of NLRP3 inflammasome components, including caspase-1 and GSDMD, thereby preserving endothelial barrier integrity and angiogenic capacity. In vivo, Lut@ZIF-8-loaded scaffolds significantly reduced inflammatory cytokine expression, enhanced collagen deposition, promoted neovascularization and re-epithelialization, and ultimately accelerated wound closure in diabetic mice. Conclusions: The pH-responsive Lut@ZIF-8 nanoplatform effectively modulates oxidative stress and endothelial cell pyroptosis in diabetic wounds, thereby promoting angiogenesis and tissue regeneration. This strategy provides a promising and innovative therapeutic approach for the treatment of chronic diabetic wounds.

Background: Nosocomial infections in patients with severe acute pancreatitis (SAP) are frequently driven by impaired intestinal barrier function, which facilitates bacterial translocation and contributes to adverse clinical outcomes. Saccharomyces boulardii (S. boulardii) can reconstitute gut microbiota composition. We investigated whether S. boulardii combined with enteral nutrition (EN) affects the microbiome and nosocomial infections in SAP. Methods: This study is a single centre, open-label randomized controlled trial. We included 50 patients with SAP in a Chinese gastroenterology intensive care unit (ICU), randomized to Probiotic group ( S. boulardii and EN) or the Control group (EN). Throat/oropharyngeal and rectal swabs were collected from patients with SAP on days 0, 1, 3, 6, 9, 12, and 15 of ICU admission. The primary endpoints were nosocomial infection and fungemia, whereas the secondary endpoints were ICU mortality, 28-day mortality, ICU stay, and length of hospital stay. All samples were subjected to full-length 16S rRNA and internal transcribed spacer (ITS) sequencing. Multivariate analysis was performed using normalized microbial and corresponding clinical data. Results: After data processing, 213 16S rRNA and 120 ITS samples were analysed. S. boulardii prevented nosocomial infections (0/27 in the Probiotic group vs 5/23 in the Control group; P < 0.05). Intestinal fungi were closely associated with nosocomial infections. Bioinformatic analysis showed that S. boulardii prevented nosocomial infections by reducing intestinal bacterial perturbation and inhibiting the proliferation of Enterococcus in the intestine, and Candida in the respiratory tract and intestines. Conclusions: S. boulardii in patients with SAP may positively alter the respiratory and intestinal microbiome and decrease the incidence of nosocomial infections. Trial registration: This study was approved by the Ethics Committee of Xinqiao Hospital, Army Medical University, Chongqing China (2021-yd030–01), which was retrospectively registered at the Chinese Clinical Trial Registry (ChiCTR2200056011, Date of Registration: 30/01/2022 https://www.chictr.org.cn/showproj.html?proj=151215).

Background: Negative pressure wound therapy (NPWT) is widely used to promote wound healing, yet the mechanotransduction mechanisms underlying its efficacy remain unclear because of the absence of precise and controllable in vitro negative pressure loading devices for cellular-level studies. Therefore, this study aims to develop a precise and controllable in vitro negative pressure loading device and to elucidate the mechanotransduction mechanism by which negative pressure activates dermal fibroblasts during wound healing. Methods: We developed a high-precision negative pressure loading device compatible with six-well plates, facilitating independent and intelligent control over negative pressure values, durations, and modes for each well. To validate the uniformity and stability of the negative pressure environment, finite element analysis (FEA) was implemented. The mechanism was explored using proteomic profiling of negative pressure-treated fibroblasts, complemented by molecular interrogation of Piezo1 expression and calcium signaling dynamics. The results of functional studies integrated genetic silencing and pharmacological modulation of the pathway, with in vivo confirmation through SD rat-based NPWT experiments. Results: FEA confirmed a stable pressure distribution within the negative pressure chamber. The cells experienced predominantly compressive stresses that scaled linearly with the applied pressure, reaching −2 kPa at −40 mmHg. We found that applying a continuous negative pressure of −40 mmHg for 2 hours significantly activated dermal fibroblasts. TMT-based proteomic analysis revealed the upregulation of Piezo1 in negative pressure-treated dermal fibroblasts, which was further confirmed by molecular and immunohistochemical analyses of both cellular and granulation tissue samples. Pharmacological inhibition or knockdown of Piezo1 attenuated negative pressure-induced dermal fibroblast activation in vivo and in vitro. Mechanistically, we determined that Piezo1-mediated Ca²⁺ influx and the calcineurin/NFAT3 signaling pathway are critically enhanced during this process. Conclusions: This study revealed that the Piezo1-Ca²⁺-NFAT3 mechanotransduction axis is the central pathway that mediates the therapeutic effects of NPWT. This work lays the foundational groundwork for elucidating the biomechanical mechanisms of negative pressure and reveals new approaches for research in tissue engineering and regenerative medicine.

As cellular energy metabolic hubs, mitochondria undergo dynamic fusion–fission cycles and autophagy that enable rapid adaptation to cellular energy demands and stress conditions. In addition to their role in energy metabolism, mitochondria are integral to cellular homeostasis and regulate cell cycle progression, differentiation, and apoptosis pathways. In recent years, the importance of mitochondrial function in skin health and disease has garnered increasing attention. Mitochondrial dysfunction has been implicated in a spectrum of skin disorders, including skin aging, psoriasis, vitiligo, keloids, scleroderma, and skin cancer. The pathogenesis of these conditions is closely linked to mitochondrial deoxyribonucleic acid (mtDNA) damage, excessive reactive oxygen species (ROS) production, and alterations in mitochondrial metabolic pathways. In terms of therapeutic strategies, this review summarizes a range of mitochondrion-targeted interventions. These treatments include the activation of the PGC-1 α pathway to increase mitochondrial adenosine triphosphate synthesis, the use of antioxidants to mitigate mitochondrial ROS production, and the application of bioactive compounds and drugs to protect mitochondria or promote mtDNA repair. These approaches not only contribute to improved skin health but also provide novel insights for the treatment of skin diseases. Additionally, mitochondrial transplantation technology has shown considerable promise in skin regeneration and wound healing and is emerging as a new frontier for skin tissue repair.

Background: Noxious lifestyle factors including spicy diets and hot baths may lead to scar formation and recurrence. These phenomena are related to the activation of the transient receptor potential vanilloid-1 (TRPV1) cation channel. Our previous study revealed significant upregulation of TRPV1 expression in the dermis of hypertrophic scar (HS), while the exact underlying mechanism of TRPV1 activation in HS remains ill-defined. This study aims to clarify the contribution of TRPV1 activation to HS pathogenesis, particularly in relation to aberrant angiogenesis. Methods: First, this study employs single-cell RNA sequencing technology to analyze the association between vascular endothelial cells and the development of HS. Complementarily, bioinformatics analysis combined with histological validation is utilized to investigate the relationship between TRPV1 channels and aberrant angiogenesis within HS formation. Furthermore, the correlation between TRPV1 activation and HS phenotypes is rigorously validated at the in vivo level. In parallel, in vitro experiments are conducted to elucidate the impact of TRPV1 channel activation on the biological behaviors and functions of vascular endothelial cells. Subsequently, key downstream signaling pathways of TRPV1 are screened, and their molecular mechanisms in regulating vascular endothelial cell-mediated angiogenesis are systematically verified. Finally, a comprehensive analysis is performed to establish the clinical relevance of the TRPV1/nuclear factor kappa-B (NF-κB)/interleukin-6 (IL-6) axis with vascularization severity and adverse prognostic outcomes in hypertrophic scarring. Results: Single-cell RNA sequencing revealed significant cellular heterogeneity in vascular endothelial cells between normal skin and HS, indicating activated angiogenesis and substantial vascular endothelial cell alterations during HS development. Bulk RNA-seq and clinical analyses further confirmed this angiogenesis activation, demonstrating a close association with TRPV1 channel activation. In vivo studies established that capsaicin (CAP)-induced TRPV1 activation exacerbated HS progression through enhanced angiogenesis, whereas TRPV1 ablation or local inhibition markedly attenuated this effect. In vitro experiments demonstrated that TRPV1 activation regulated angiogenesis by promoting pro-angiogenic phenotypes. Transcriptomic analysis and functional validation identified the IL-6/signal transducer and activator of transcription 3 pathway as a downstream NF-κB-dependent pro-angiogenic axis mediated by TRPV1 in HS vascular endothelial cells. Critically, dermal overexpression of the TRPV1/NF-κB/IL-6 axis in HS patients correlated strongly with both disease severity and recurrence. Conclusions: Here, we show that the development of HS is strongly correlated with endothelial angiogenic activity. TRPV1 activation by CAP enhances proangiogenic processes including endothelial proliferation, migration, and tubule formation, while reducing apoptosis through the TRPV1/NF-κB/IL-6 axis. In a rabbit ear HS model, stimulation of TRPV1 contributes to the formation of HS via the TRPV1/NF-κB/IL-6 axis, whereas pharmacological ablation of TRPV1 significantly reversed these phenotypes. These findings shed light on the underlying molecular mechanisms and provide a potential therapeutic target for HS.

Wound healing is a highly coordinated biological process traditionally divided into three phases: inflammatory, proliferative, and remodeling. Diabetes and acute trauma markedly disrupt these stages, resulting in delayed wound closure, persistent inflammation, and impaired tissue regeneration. This review focuses on three trauma-relevant contexts: (i) skin wounds, including diabetic ulcers and burns; (ii) bone fracture healing; and (iii) corneal epithelial and stromal injury. Robust in vivo evidence is synthesized to delineate the mechanistic roles of the four principal ribonucleic acid (RNA) modifications: N⁶-methyladenosine, 5-methylcytosine, N⁷-methylguanosine, and N⁴-acetylcytidine. Additionally, the roles of RNA modification writers, erasers, and readers in regulating macrophage polarization, stem and progenitor cell fate, angiogenesis, lymphangiogenesis, and extracellular matrix remodeling are examined. Evidence across different tissues and wound healing phases is integrated rather than presented descriptively. Methodological limitations are highlighted, and knowledge gaps are identified alongside testable hypotheses. Translational opportunities with direct relevance to burn and trauma management are emphasized. This review aims to integrate mechanistic and translational insights into a coherent framework for therapeutic intervention. By defining how RNA modifications intersect with distinct wound healing phases, concrete therapeutic entry points and delivery strategies relevant to burns and trauma are identified, including topical hydrogels, exosome-based therapies, and bone-targeted nanoparticles. Designs for pragmatic clinical trials and biomarker strategies that enable translation of preclinical findings to patients are also discussed.

Background: Traumatic brain injury (TBI) can cause neuroinflammation and neuronal death. The role of mitochondrial dysfunction in regulating inflammasome activation during TBI remains unclear. This study aims to explore mitochondrial regulation of neuroinflammation and pyroptosis after TBI. Methods: We used a mouse TBI model and in vitro scratch-injured HT22 cells and primary neurons to examine changes in mitochondrial dynamics and nucleotide-binding oligomerization domain-like receptors family pyrin domain-containing 3 (NLRP3) inflammasome activation. Metformin treatment, mitofusin 1 (Mfn1) knockdown and regulation of the Mfn1 pathway were applied to evaluate the therapeutic effects and mechanisms. Results: TBI triggered NLRP3 inflammasome activation and neuronal pyroptosis, along with impaired mitochondrial function and oxidative stress. Metformin reduced inflammasome activation, improved mitochondrial homeostasis, and alleviated neuronal injury. These effects were lost when Mfn1 was silenced, highlighting its essential role. Furthermore, we determined that the AMPK pathway modulates these observed effects. Conclusion: Metformin protects against TBI-induced neuronal damage by restoring Mfn1-dependent mitochondrial dynamics and suppressing inflammasome activation. Mfn1 is a key mediator linking mitochondrial health to neuroinflammatory responses in TBI.

Background: Random skin flap application is considerably limited by postoperative complications, particularly distal tissue ischemia and necrosis. Melatonin, a molecule with well-documented antioxidant and cytoprotective properties, has shown promise in protecting ischemic tissues. However, its specific role in regulating ferroptosis during ischemic flap injury, as well as its safety and efficacy in primate models (a key step for clinical translation), remains to be systematically validated. In this study, we aimed to promote angiogenesis within flap tissue through exogenous melatonin administration and to inhibit ferroptosis to mitigate ischemia–reperfusion injury, presenting a novel strategy for enhancing flap survival rates. Methods: A random skin flap was constructed in C57BL/6J mice. After melatonin treatment for seven days, the influence of melatonin on the levels of oxidative stress, iron accumulation, and mitochondrial morphology within the skin flap tissue was assessed. We used Transwell migration assays, tube formation assays, flow cytometry, and immunofluorescence staining to determine the effects of melatonin in vitro. The ferroptosis inducer erastin was used in combination with melatonin to treat random skin flap mice and tert-butyl hydroperoxide (TBHP)–induced cellular models, and the pathway through which melatonin counteracts iron mutations was explored. Lastly, we conducted experiments using nonhuman primate models and analyzed the protective effects of melatonin on ischemic flaps in macaques, highlighting its potential for clinical translation. Results: Melatonin ameliorated the survival area of ischemic flaps in mice, enhanced angiogenesis, reduced mitochondrial damage, and also suppressed lipid peroxidation and iron ion accumulation. Melatonin attenuated TBHP-induced cell death, lipid peroxidation, and mitochondrial damage in vitro. Further mechanistic studies revealed that melatonin inhibited ferroptosis, accompanied by nuclear translocation of nuclear factor E2-related factor 2 (Nrf2), and increases the expression of downstream gene (effector) heme oxygenase-1 (HO-1). More importantly, experiments in macaques demonstrated that melatonin could enhance flap viability and angiogenesis, and exhibited a good safety profile. Conclusion: Melatonin enhanced flap viability in mice and macaques by inhibiting ferroptosis, boosting angiogenesis, and attenuating oxidative stress injury.

Background: Persistent local tissue hypoperfusion and chronic inflammation are central challenges in diabetic wound management. The development of effective therapeutic strategies to mitigate prolonged inflammation and enhance tissue vascularization is crucial for accelerating diabetic wound healing. This study aimed to develop soluble microneedle materials that simultaneously target both aspects to improve the clinical prognosis of diabetic wounds. Methods: A stable macrophage cell line overexpressing basic fibroblast growth factor (bFGF) was established using lentiviral transfection. After M2 polarization was induced with interleukin-4 (IL-4) and IL-10, exosomes were isolated via ultracentrifugation and surface-functionalized with arginine-glycine-aspartic acid (RGD)-targeting peptides. The reparative effects of these exosomes on human umbilical vein endothelial cells (HUVECs) with high glucose-induced injury were evaluated using scratch test, 5-ethynyl-2′-deoxyuridine (EdU) staining, and cell counting kit-8 assays. A delivery system based on soluble hyaluronic acid microneedles (MNs) loaded with engineered exosomes was then developed. Its therapeutic efficacy was evaluated in a diabetic wound mouse model, and the underlying mechanisms were explored via ribonucleic acid (RNA) sequencing. Results: Targeted engineered exosomes (TE-Exos) derived from bFGF-overexpressing M2 macrophages with surface RGD modification were successfully prepared. Assays revealed that TE-Exos exhibited specific targeting to HUVECs with high glucose-induced injury and significantly enhanced cellular proliferation, migration, and tube formation. Furthermore, the polarization ratio of macrophages improved after TE-Exos treatment. In vivo, the MN-mediated delivery of TE-Exos markedly accelerated diabetic wound healing by enhancing re-epithelialization, collagen deposition, and angiogenesis. Furthermore, the treatment modulated the wound microenvironment by reducing the infiltration of proinflammatory M1 macrophages while increasing the proportion of reparative M2 macrophages. RNA sequencing analysis indicated that the therapeutic effects were mediated primarily through the inhibition of excessive inflammation and the activation of angiogenesis-related signaling pathways. Conclusions: This innovative strategy breaks the vicious cycle of impaired angiogenesis and chronic inflammation in diabetic wounds through a synergistic mechanism involving ‘angiogenesis, inflammation regulation, and precise delivery’. The combination of targeted exosome engineering with an MN delivery system not only overcomes the limitations of conventional growth factor therapies but also enables intelligent modulation of the wound microenvironment, offering novel theoretical insights and practical approaches for clinical translation.

As three-dimensional biomimetic systems developed from stem cells or somatic cells, organoids have gradually evolved into important links between basic research and clinical application. Compared with traditional two-dimensional culture and animal models, organoids can better reflect the structure and function of tissues and organs in terms of physiological relevance and prediction efficiency. This review explores the integration of organoid technology with microfluidic technology, gene editing, and artificial intelligence, focusing on the prospects of these technologies for application in precision medicine, disease modelling, drug screening, and toxicology. In addition, the latest progress in organoid research, including organ-on- a-chip, organoid biobank construction, and related applications of regenerative medicine, is summarized. The development of key technologies is reviewed in detail. These technologies include improvements in culture systems, innovations in microfluidic and matrix materials, gene editing and modification, and imaging and multiomic analyses. These achievements improve the application value of organoids in disease modelling, drug screening, and toxicology. Despite challenges such as standardization, batch-to-batch consistency, and clinical translation, the integration of interdisciplinary technologies has provided a new impetus for the development of organoids. In the future, the combination of organoids with artificial intelligence, personalized medicine, and regenerative medicine is expected to drive research progress on disease mechanisms and precision treatment.

Background: Current methods used for assessing random-pattern skin flaps (RPSFs) viability are invasive and subjective. Therefore, this study aimed to establish an accurate and non-invasive method for predicting RPSFs prognosis using skin barrier monitoring technology. Methods: Gene ontology (GO) analysis was employed to identify the potential pathways associated with RPSFs necrosis. Skin barrier monitoring technology, immunohistochemistry (IHC), immunofluorescence (IF), and western blotting (WB) were employed to assess skin barrier integrity, quantify ferroptosis level, and evaluate the recruitment of M1 macrophages and regulatory T cells (Tregs). Clinical samples were also included to validate the accuracy and efficacy of skin barrier monitoring technology in predicting RPSFs necrosis. Results: The necrotic process in RPSFs was characterized by increased infiltration of M1 macrophages and Tregs, accompanied by activated ferroptosis and dysfunction of skin barrier. Notably, Tregs infiltration significantly reduced the necrotic area and restored skin barrier integrity of RPSFs by inhibiting ferroptosis and polarization of M1 macrophages. Mechanistically, USP4 regulated the interaction of M1 macrophages and Tregs (M1 macrophages -Tregs axis) via stabilization of TNFAIP2. Analysis of clinical samples revealed that skin barrier monitoring technology could serve as predictive strategy for RPSFs necrosis. Conclusions: This study demonstrated that the USP4/TNFAIP2 pathway would regulate skin barrier function and ferroptosis via ‘M1 macrophages -Tregs axis’ in RPSFs. And the skin barrier monitoring technology could serve as reliable method for RPSFs necrosis prediction.

The rising global prevalence of chronic conditions, notably obesity and type 2 diabetes, demands innovative approaches to mitigate their health and economic impacts. Complications, including neuropathy and chronic limb-threatening ischemia (CLTI), dramatically increase the risk of lower limb amputation, cardiovascular events, and cerebrovascular events, underscoring the urgent need for effective interventions. Emerging neuromodulation and regenerative strategies provide novel approaches to addressing diabetes-related complications. High-frequency (10-kHz) spinal cord stimulation demonstrates marked pain relief and sensory improvement in patients with refractory painful diabetic neuropathy. Peripheral focused ultrasound, including splenic-targeted stimulation, shows promise in reducing systemic inflammation, accelerating wound repair, and enhancing vascular function. Remote ischemic conditioning leverages brief controlled ischemic reperfusion cycles to enhance microcirculation and promote diabetic foot ulcer (DFU) healing. In severe cases, surgical techniques such as tibial transverse transport and lateral tibial periosteum distraction stimulate angiogenesis and enhance distal limb perfusion. Integrated wound care protocols, incorporating these procedures alongside debridement, negative pressure wound therapy, and skin grafting, may further optimize outcomes. Collectively, these therapies address both local and systemic pathophysiology, frequently producing physiologic effects at sites distant from the primary intervention. These seemingly disparate therapies represent a single unifying concept: generating a physiologic effect at locations remote from the primary target. This systematic approach, engaging neural, vascular, and immune pathways, may be key to improving outcomes in DFUs and CLTI. Early clinical data appears promising; however, larger randomized trials are required to validate efficacy, refine patient selection, and determine optimal integration with standard care. If confirmed, these strategies may shift management toward patient-centered, regenerative interventions that preserve limbs, reduce recurrence, and enhance quality of life for the expanding global patient population. Further research is warranted to confirm or refute these early promising physiologic effects.

Diabetic wounds are a major clinical challenge. They are driven by persistent hyperglycemia and chronic inflammation that synergistically disrupt mitochondrial homeostasis, manifesting as impaired bioenergetics, excessive reactive oxygen species (ROS) accumulation, and dysregulated mitochondrial quality control. Mitochondrial dysfunction critically undermines cellular proliferation, angiogenesis, and immunomodulation, which are essential for effective tissue repair. Intercellular mitochondrial transfer, mediated through tunneling nanotubes (TNTs), extracellular vesicles (EVs), gap junctions (GJs), and cell fusion, has recently emerged as a biologically compelling endogenous rescue mechanism capable of restoring bioenergetic capacity and redox homeostasis in metabolically compromised recipient cells. In this review, we systematically examine the mechanistic basis of mitochondrial dysfunction in the diabetic wound microenvironment, critically evaluate the therapeutic potential of intercellular mitochondrial transfer, and propose an integrated mechanism-to-translational framework coupling transfer-based strategies with bioresponsive and mitochondrion-targeted biomaterials tailored to the pathological wound milieu. Furthermore, we identify key translational barriers-including insufficient protocol standardization, the absence of robust characterization criteria, and a lack of quantitative benchmarks for transfer efficacy-that must be addressed to advance these strategies toward clinical application, thereby offering a conceptual foundation and translational roadmap for mitochondrion-centered regenerative approaches in diabetic wound care.

Skin shows distinct temporal dynamics and spatial heterogeneity during development, aging, disease, and regeneration. Although single-cell sequencing has revealed cellular diversity, its lack of spatial context limits the ability to characterize cells within their native tissue microenvironment. Factors such as acute injury and chronic wounds spatiotemporally disrupt skin homeostasis and induce complex remodeling and functional changes. Understanding these dynamic processes with spatiotemporal resolution remains a challenge in skin biology. Recent advances in spatiotemporal omics make it possible to integrate single-cell sequencing, spatial omics, and time series analyses, allowing the preservation of in situ cellular positions and revealing gene expression dynamics and intercellular networks. These technologies have reshaped the understanding of skin development and wound healing and have promoted advances in precision medicine and regenerative therapies. In this review, the applications of, recent advances in, and clinical translation potential of spatiotemporal omics in skin research are summarized. The construction of a high-resolution, spatiotemporal cellular atlas across the human skin life cycle will help identify key biomarkers, optimize regenerative strategies, and support personalized therapies.

Background: Fibrotic scar formation constitutes a significant pathological obstacle that impedes neural regeneration and long-term functional recovery following spinal cord injury (SCI). However, the spatial distribution of key pro-fibrotic mediators within lesion scars and the upstream regulatory mechanisms driving fibroblast activation remain inadequately defined. This study aims to characterize CD36-associated fibrotic remodeling after SCI and to determine whether targeting the c-Jun–Irf8–CD36 axis could attenuate scar formation, improve the regenerative microenvironment, and promote functional recovery. Methods: This study integrated single-cell ribonucleic acid sequencing and spatial transcriptomic profiling to characterize CD36 expression patterns and identify fibroblast subpopulations within SCI scars. Pharmacological interventions were administered in mouse SCI models, using salvianolic acid B (SAB) to inhibit CD36 and T5224 to block AP-1/c-Jun activity. Histological and immunofluorescence analyses were performed to assess fibroblast accumulation, extracellular matrix deposition, angiogenesis, and axonal regeneration, alongside longitudinal behavioral evaluations of locomotor function. Mechanistic validation of the regulatory pathway was achieved through CUT&Tag and dual-luciferase reporter assays to investigate c-Jun–Irf8–CD36 transcriptional regulation, complemented by integrated single-cell/spatial analyses to assess fibroblast subcluster remodeling post-treatment. Results: Spatial and single-cell analyses demonstrated that CD36 is predominantly localized within lesion scars, correlating with fibrotic progression and preferentially upregulated in specific fibroblast subclusters. SAB-mediated CD36 inhibition markedly reduced P4HB⁺ fibroblast accumulation, alleviated fibrotic deposition, enhanced angiogenesis and axonal regeneration, and improved hindlimb functional recovery. Mechanistically, c-Jun was upregulated in scar regions and indirectly promoted CD36 transcription through Irf8 activation, establishing a c-Jun–Irf8–CD36 signaling axis. CUT&Tag and reporter assays confirmed c-Jun binding to the Irf8 promoter, leading to Irf8-driven CD36 transcription. Similarly, T5224 downregulated CD36 expression, reduced fibroblast aggregation and matrix deposition, facilitated vascular remodeling, and promoted early functional recovery. These findings demonstrate that modulating this signaling pathway can significantly inhibit pathological scar formation and facilitate approximately scar-free healing, thereby providing an ideal microenvironment for tissue regeneration. Multi-omic analyses further revealed that T5224 selectively inhibited the aberrant expansion of CD36⁺ fibroblast subclusters and reprogrammed their transcriptional states toward a less fibrotic phenotype. Conclusions: The c-Jun–Irf8–CD36 axis serves as a pivotal regulator of fibrotic scar formation after SCI. Targeting this pathway through CD36 inhibition (SAB) or AP-1/c-Jun blockade (T5224) attenuates fibrosis, remodels the scar microenvironment, enhances tissue repair, and promotes functional recovery, highlighting a promising therapeutic strategy for central nervous system injury.

Background: Diabetic foot ulcer (DFU) is a severe diabetic complication characterized by impaired healing, often involving fibroblast senescence and the senescence-associated secretory phenotype (SASP). The role of ribonucleic acid (RNA)-binding proteins (RBPs) in this process remains undefined. This study investigates the function and mechanism of the RBP interleukin enhancer-binding factor 2 (ILF2) in DFU pathogenesis. Methods: Differentially expressed RBPs were identified via bioinformatics analysis of public single-cell and bulk transcriptomic datasets. ILF2 downregulation was subsequently validated in clinical DFU samples and diabetic mouse models. Functional assays in high-glucose (HG)-treated fibroblasts evaluated proliferation, migration, and SASP. Mechanistically, RNA sequencing, RNA-binding protein immunoprecipitation, and RNA pull-down assays identified downstream targets, while co-IP and rescue experiments verified the NPM1/NF-κB axis. Finally, a diabetic mouse model was used to study the effects of ILF2 overexpression/knockdown and NPM1 knockdown on wound healing. Results: Bioinformatics analysis identified ILF2 as significantly downregulated in DFU. This reduction was consistently validated in DFU patient tissues, diabetic mouse wounds, and HG-treated fibroblasts. Functionally, ILF2 overexpression promoted fibroblast proliferation and migration while suppressing SASP, whereas knockdown exacerbated senescence. Mechanistically, ILF2 directly bound to nucleophosmin (NPM1) mRNA to promote its degradation. ILF2 deficiency led to aberrant NPM1 accumulation, enhancing the NPM1–phospho-p65 interaction and NF-κB pathway activation. Rescue experiments confirmed that NPM1 knockdown reversed ILF2 deficiency-induced cellular dysfunction. Crucially, these findings were validated in primary fibroblasts isolated from DFU patients. In vivo, ILF2 overexpression accelerated wound healing, while knockdown delayed the process. Furthermore, NPM1 knockdown effectively ameliorated the impaired healing phenotype and reduced SASP levels. Conclusions: This study elucidates a novel ILF2–NPM1–NF-κB regulatory axis. ILF2 acts as a critical suppressor of inflammatory senescence by destabilizing NPM1 mRNA, highlighting its potential as a therapeutic target for DFU treatment.

Ischaemia–reperfusion injury (IRI) is a fundamental pathological process underlying acute and chronic damage associated with myocardial infarction, ischaemic stroke, and solid organ transplantation. Although timely reperfusion is indispensable for tissue salvage, it paradoxically promotes maladaptive immune activation and oxidative stress, which aggravate microvascular dysfunction and organ failure. Accumulating evidence indicates that sterile inflammation, endothelial injury, and immunothrombosis are the central drivers of IRI progression. Among innate immune effectors, neutrophils act as first responders that integrate chemotactic signalling, adhesion cascades, and metabolic rewiring. Upon activation, neutrophils release damage-associated molecular patterns and form neutrophil extracellular traps (NETs), which amplify inflammation, promote coagulation, and disrupt tissue repair across organs. However, the organ-specific roles, temporal dynamics, and translational relevance of neutrophils and NETs in IRI remain incompletely understood. In this review, we systematically dissect the neutrophil-and NET-mediated mechanisms involved in IRI across the heart, brain, kidney, liver, and transplanted organs, with a particular emphasis on endothelial crosstalk, immunothrombosis, and metabolic regulation. We further summarize emerging NET-associated biomarkers-including cell-free DNA and myeloperoxidase–DNA complexes-for IRI diagnosis and prognosis. Finally, we evaluate therapeutic strategies targeting neutrophil recruitment, immune metabolism, and NET clearance, highlighting challenges for clinical translation. In summary, this review provides a mechanistic and translational framework for targeting neutrophils and NETs in precision therapies for IRI.

Bleeding, a critical complication in trauma, surgery, and conditions such as hemophilia, liver cirrhosis, and thrombocytopenia, often leads to shock or death. The limitations of traditional hemostatic methods-such as compression, suturing, and electrocautery-have prompted the development of advanced biomaterials. In modern research, intelligent, multi-mechanism systems have supplanted basic physical or chemical approaches. Biomimetic designs, such as platelet- and fibrin-inspired materials, alongside nanotechnology (e.g. nanoparticle carriers and electrospun fibers) and stimuli-responsive polymers (e.g. light- or temperature-triggered), enable targeted clotting, controlled drug release, and enhanced wound adhesion. Additionally, 3D printing and microfluidics allow precise material modification, further boosting hemostatic efficiency. Despite these advances, clinical translation faces challenges related to biocompatibility, mass production, and patient-specific customization. Future progress is likely to integrate multidisciplinary technologies, such as artificial intelligence, genetic engineering, smart regulation, and personalized therapies, to improve hemorrhage management. These innovations aim to bridge the gap between laboratory research and clinical application, offering safer, more effective solutions for trauma and surgical interventions.

Hypertrophic scars (HS) represent a significant clinical challenge due to their complex pathophysiology and resistance to conventional therapies, often resulting in persistent symptoms such as itching, pain, and impaired joint mobility that compromise patients’ quality of life. Current treatment modalities, including compression therapy, pharmacological agents, radiation, silicone gel, and laser therapies, have faced limitations primarily due to inadequate drug penetration into the dense fibrotic scar tissue. In this context, microneedle-mediated controlled delivery systems have emerged as a promising pharmaceutical platform to enhance localized and sustained delivery of therapeutic agents, including small-molecule drugs, biologic proteins, small interfering RNA, and living cells, directly into HS. This article critically reviews the biological and formulation-related challenges associated with transdermal delivery in scar tissue and highlights recent innovations in microneedle design, material selection, and drug-loading techniques tailored for controlled release applications. Furthermore, it discusses the integration of proteins and cell-based therapies within microneedle platforms and their potential to modulate scar remodeling and inflammation. By addressing current limitations and exploring cutting-edge technologies, this review article aims to guide the development of effective microneedle-mediated strategies for pharmaceutical intervention in hypertrophic scar management.

Emergency and critical care medicine requires the rapid synthesis of heterogeneous clinical data under extreme time constraints. Early artificial intelligence tools lacked the flexibility to manage real-world patient heterogeneity. Large language models (LLMs) offer a paradigm shift by demonstrating advanced natural language understanding, cross-task generalization, and context-sensitive reasoning, thereby bridging the gap between fragmented algorithms and holistic clinical decision support. The effective deployment of these models is grounded in four methodological pillars: domain adaptation, knowledge integration, multimodal and temporal modeling, and transparency. Domain adaptation and knowledge integration specifically empower the context-sensitive reasoning required for high-stakes intensive care. This theoretical framework enables their application across clinical decision support, documentation optimization, medical education, and clinical research. Integrating continuous physiological waveforms with multi-omics data facilitates dynamic risk stratification for complex conditions like sepsis, while natural language-to-structured query language capabilities accelerate clinical data extraction and quality improvement. The transition of LLMs from experimental settings to routine clinical deployment remains constrained by model hallucinations, multimodal integration barriers, and unresolved ethical governance. Sustainable implementation requires a human-in-the-loop copilot design, rigorous multicenter prospective validation, and transparent regulatory frameworks. Addressing these challenges is essential to ensure that technological innovations safely translate into measurable improvements in patient survival and clinical outcomes.

Background: Hypertrophic scars (HTSs) are characterized by excessive extracellular matrix deposition and impaired scar remodelling. Fibroblasts are central to HTS pathogenesis, yet clinical strategies remain limited by an incomplete understanding of fibroblast heterogeneity and transcriptional regulation. This study aimed to identify a key fibroblast subpopulation and its regulatory transcription factors to address this translational gap. Methods: Single-cell RNA sequencing was performed on dermal cells from freshly excised human HTS and normal skin (NS) tissues. Fibroblast subsets and transcriptional regulators were identified using Seurat, pseudotime, transcription factor prediction, and cell–cell communication analyses. Functional validation involved lentiviral overexpression of Yin Yang 1 (YY1) in fibroblasts derived from patients with hypertrophic scars, followed by bulk RNA sequencing, western blotting, CUT&Tag, and immunofluorescence assays. Results: Clinical HTS specimens showed characteristic collagen overproduction and vascular hyperplasia. Single-cell analysis of 43 303 cells revealed disease-specific shifts in cellular composition, including pronounced pericyte expansion and reduced fibroblast abundance. Notably, fibroblast subcluster Fib_5 (ADAM12⁺COMP⁺POSTN^hi) increased despite the overall fibroblast decline in HTS and exhibited upregulated fibrotic gene expression. Cross-validation using combined public datasets comprising 21 samples indicated that the Fib_5-like subcluster is conserved across fibrotic conditions. Pseudotime analyses placed Fib_5 within an HTS-dominant branch, State 6; transcription factor prediction from branch-dependent differentially expressed genes identified YY1 as the only predicted transcription factor also differentially expressed in State 6. Functional validation showed that YY1 overexpression in fibroblasts derived from patients with HTS reversed fibrotic gene expression profiles, with Fib_5 identified as a primary responder by Scissor. CUT&Tag analysis validated these findings at the epigenomic level. Cell–cell communication analyses further revealed marked reprogramming of fibroblast-pericyte signalling across multiple fibrosis-related pathways in HTS. Conclusion: This work establishes the Fib_5-YY1 axis as a central hub in HTS pathogenesis, with YY1-mediated fibroblast plasticity as a key transcriptional mechanism underlying skin fibrogenesis.

Necrotizing soft tissue infections (NSTIs) represent a group of rapidly progressing, life-threatening infections characterized by widespread tissue necrosis, systemic inflammation, and multiorgan failure. Early diagnosis remains a clinical challenge because of nonspecific initial manifestations and overlapping symptoms with other soft tissue infections. Diagnostic scoring systems such as the Laboratory Risk Indicator for Necrotizing Fasciitis score and its variants have been widely utilized to facilitate early recognition but are limited by variable sensitivity and insufficient predictive value across diverse clinical populations. Recent advances in multi-omics technologies and machine learning approaches have enabled the identification of molecular biomarkers and predictive patterns associated with NSTI onset and progression. Integration of high-dimensional omics data with clinical and imaging parameters holds potential for dynamic, real-time diagnostic support, and individualized risk stratification in the intensive care setting. This review summarizes the evolution of diagnostic strategies for NSTIs, criti- cally appraises the limitations of conventional clinical scoring systems, and examines emerging omics-based and ML-driven approaches. Finally, we propose an integrated diagnostic roadmap that aligns clinical assessment, imaging, microbiologic evaluation, host-response biomarkers, and multi-omics data to guide future research and clinical translation.

The integrity of the intestinal mucosal barrier is essential for maintaining normal gut physiology, and its disruption is associated with a wide range of conditions, including trauma-and burn-related intestinal injury, which remain difficult to manage clinically. Intestinal organoid-on-a-chip systems have emerged as advanced in vitro models that reproduce key features of the intestinal microenvironment and physiological function. These systems have shown promise for studying mucosal injury and repair, assessing therapeutic strategies, and supporting translational research. This review summarizes the basic principles of intestinal organoid-on-a-chip technology and examines its use in modeling intestinal barrier function, inflammatory responses, drug screening, regenerative approaches, and trauma-related barrier repair. It also reviews recent progress in preclinical studies, considers potential applications in gastrointestinal research, and discusses current technical challenges, particularly those related to scalability and reproducibility. Future directions for the development of next-generation systems are also outlined. With the continued integration of advances across disciplines, these platforms may provide useful tools for studying and treating disorders involving the intestinal mucosal barrier, especially in the context of trauma and burns.

Regenerative medicine is undergoing a paradigm shift from live-cell therapies to cell-free strategies. Within this evolving field, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a leading platform. These nanoscale vesicles deliver bioactive cargo that mediates critical therapeutic functions, including immunomodulation, angiogenesis, and anti-fibrosis. Furthermore, they offer improved safety, greater potential for standardization, and enhanced scalability compared to traditional live-cell therapies. However, clinical translation remains constrained by several challenges, such as inherent vesicle heterogeneity, limited targeting specificity, and bottlenecks in large-scale manufacturing. This review systematically examines the biogenesis of MSC-EVs, focusing specifically on exosomes, microvesicles, and apoptotic vesicles. We evaluate their functional performance across diverse regeneration contexts, encompassing orofacial, barrier, musculoskeletal, and visceral tissue regeneration. We further highlight innovative engineering strategies designed to enhance therapeutic efficacy, such as surface modification, cargo loading, and biomaterial-integrated delivery systems. In addition, we introduce an emerging approach utilizing engineered MSC aggregate-derived EVs inspired by organ morphogenesis. Finally, this article details the strategic framework required for clinical translation. The framework encompasses scalable production, rigorous quality control, comprehensive non-clinical studies, evolving regulatory pathways, and the current clinical trial landscape. Collectively, this work provides an integrated roadmap for advancing MSC-EVs as a next-generation precision platform for cell-free therapeutics.

Regenerating complex human tissues requires proper cellular assembly and the recapitulation of coordinated functions across multiple biological levels. Organoids, as self-organized three-dimensional cellular structures, provide powerful models for rebuilding organ architecture and studying developmental processes. However, their regenerative potential remains limited by the lack of vascular, neural, and immune integration, which are essential for tissue development, homeostasis, and repair. Recent studies indicate that the progression from tissue-level organization to organ-level coordination and ultimately to system-level functionality depends on dynamic intercellular communication, feedback signaling, and niche interactions. The integration of biochemical, biomechanical, and bioelectrical cues enables multicellular systems to achieve synchronized growth, patterning, and functional adaptation. Complementary bioengineering strategies further guide these intrinsic processes by modulating spatial organization, microenvironmental signals, and intercellular connectivity. This review summarizes emerging methodologies and molecular mechanisms underlying system-level integration in organoids and discusses how these biological processes may bridge the gap between in vitro morphogenesis and in vivo functional regeneration.

Wound healing is essential for maintaining organismal homeostasis and barrier function, posing significant challenges particularly in the management of hard-to-heal wounds such as diabetic ulcers. This review systematically summarizes the functional properties of piezoelectric electrospun biomaterials and their biological mechanisms in promoting wound healing via electrical stimulation (ES). Piezoelectric nanofiber wound dressings fabricated by electrospinning technology offer dual advantages: on one hand, their unique fibrous architecture enables adaptation to irregular wound contours, facilitates rapid hemostasis, and provides an effective barrier against microbial invasion; on the other hand, their inherent piezoelectric effect converts micromechanical deformations into localized electrical signals in real time, thereby modulating cellular behaviors and accelerating tissue repair. This review highlights recent studies elucidating the mechanisms by which ES promotes wound healing, and the functional characteristics of piezoelectric fibrous dressings. It aims to establish a theoretical foundation for the rational design and performance optimization of next-generation intelligent piezoelectric wound dressings, thereby advancing their clinical translation and industrial development.

Background: Burn injuries affect the central nervous system, and evidence suggests they induce changes in cortical excitability related to motor dysfunction. The current study investigated markers of neuroplasticity in the motor cortex and motor performance in the subacute period following burn injury. Methods: Thirty-four patients with a non-severe burn injury (total body surface area: 1.0 ± 2.0%; 16 females; age: 46.0 ± 14.0 years) participated in a longitudinal study with assessments ranging from ~1 to ~17 weeks post-injury. Transcranial magnetic stimulation was used to evaluate motor cortex excitability and short-and long-intracortical inhibition (SICI; LICI) before and after application of paired associative stimulation (PAS) to induce neuroplasticity. Motor performance was assessed using the Purdue Pegboard. Results: Patients showed improvements in bilateral motor performance from ~3 to ~6 weeks post-injury. PAS did not induce any change in net motor cortex excitability or SICI but increased LICI, which was greatest ~6 weeks post-injury. Adjusted modeling showed that greater PAS-induced increase in LICI was associated with better bilateral motor performance, suggesting an association between PAS-induced neuroplasticity of long-acting inhibitory circuits in the primary motor cortex and motor function following burn injury. Conclusions: The data provide a neurophysiological basis to test whether targeting inhibitory networks in the subacute period after burn injury can enhance or expedite functional recovery.

Diabetic foot ulcers (DFUs) represent a growing clinical challenge, driven by an aging global population and the increasing prevalence of diabetes. Affecting millions worldwide, DFUs remain one of the most serious complications of diabetes, frequently progressing to infection, amputation, and elevated mortality. Standard treatments typically include pressure offloading, circulation improvement, infection control, and topical wound care; however, many chronic DFUs fail to respond to these interventions due to persistent inflammation, impaired vascularization, and microbial burden. These challenges have accelerated interest in regenerative medicine approaches, including stem cells, growth factors, and skin substitutes. Among these, skin substitutes have shown particular promise; among Food and Drug Administration-approved options, products such as the collagen-Manuka honey-hydroxyapatite patch from SweetBio (Apis^®) have demonstrated improved outcomes in patients with chronic ulcers. Silk fibroin (SF), a natural biopolymer with established clinical use, has emerged as a promising platform for chronic wound management due to its biocompatibility, tunable degradation, and capacity for controlled bio-additive delivery. SF scaffolds can be fabricated through various methods tailored to wound-healing applications: electrospun fibrous mats with high surface-area-to-volume ratio, freeze-dried porous constructs with interconnected architecture, and hydrogels designed for controlled drug delivery. In this review, we critically examine how SF scaffolds enhanced with bio-additives modulate cellular responses, redirect dysregulated healing pathways, accelerate wound closure, and promote tissue regeneration in diabetic wounds. We synthesize recent advances in preclinical and clinical studies, identify key translational barriers, and outline future directions for advancing SF-based dressings toward clinical adoption. Collectively, this review positions bio-enhanced SF scaffolds as next-generation, disease-informed candidates for improving outcomes in chronic DFU care.

Background: Severe acute kidney injury (AKI) is associated with high mortality. Current blood purification technologies fail to replace the biological functions of renal tubular epithelial cells (RTECs), such as active transport, acid–base homeostasis, and endocrine regulation. The integration of viable RTECs into an extracorporeal circuit to construct a bioartificial kidney represents a potential strategy for renal functional support. However, its translation is constrained by the rapid loss of seed cell phenotypes, immune and coagulation activation triggered by conventional materials, and a lack of in vivo validation in large animal models. However, three key challenges hinder its clinical translation, which this study seeks to address: the rapid loss of seed cell phenotypes, immune and coagulation activation triggered by conventional materials, and a lack of in vivo validation in large animal models. Methods: We engineered a renal tubule assist device (RAD) that integrates viable cells with a functionalized interface. First, we established an immortalized human proximal tubule cell line [immortalized renal tubular epithelial cell line (iRTEC)] and achieved scalable expansion using a microcarrier system. Second, we fabricated a cell-supporting interface [chlorogenic acid/poly-L-lysine-modified pristine nanofibrous membrane (CA/PLL-PNF)] with antioxidant properties and enhanced hemocompatibility via the layer-by-layer self-assembly of PLL and CA onto polyacrylonitrile nanofibrous membranes. Finally, we assembled these components into a flat-plate bioreactor and evaluated its extracorporeal performance in a Bama miniature pig model after bilateral nephrectomy. Results: iRTECs were stably expanded on microcarriers while maintaining a proximal tubule phenotype, and these cells outperformed existing cell lines in terms of amino acid hydrolysis and transmembrane transport, acid–base regulation, water transport, and endocrine responsiveness. With respect to the supporting interface, CA/PLL-PNF effectively scavenged diverse free radicals and mitigated cellular oxidative stress. Proteomic analysis confirmed that this modification remodeled the plasma protein corona, which significantly reduced the adsorption of complement and coagulation factors. In the bilaterally nephrectomized pig model, the RAD safely maintained extracorporeal circulation for 4 h-the duration of routine clinical dialysis-and preserved internal homeostasis. The antioxidant interface significantly attenuated circulating lipid peroxidation during treatment. Compared with hemofiltration alone, the RAD significantly enhanced the clearance of middle-molecule toxins (β₂-microglobulin) and reduced proinflammatory cytokine levels at the outlet, demonstrating its capacity for the active modulation of local inflammation. Conclusions: This study established a renal support platform that integrates viable cells and functional materials. The device exhibited multidimensional biological efficacy in toxin clearance and internal homeostasis regulation and achieved stable extracorporeal circulation in a preclinical large animal model, which provides experimental evidence for advanced organ support strategies in the setting of severe AKI.

The mitochondrial unfolded protein response (UPR^mt) is a conserved mitochondrial stress response that is activated by mitochondrial dysfunction to maintain proteostasis. Although UPR^mt has been extensively studied in aging and cancer, its role in trauma and critical illness remains poorly understood. Here, we propose a unifying conceptual framework in which UPR^mt functions as a central stress-integration hub that senses and coordinates adaptive responses following acute injury. We systematically review the mechanisms of UPR^mt activation triggered by diverse insults and highlight how UPR^mt integrates mitochondrial-nuclear communication, and crosstalk with other stress-responses such as the integrated stress response and mitophagy. Beyond cell-autonomous regulation, UPR^mt also coordinates systemic adaptation through mitokine-mediated interorgan signaling. Importantly, we emphasize the context-dependent role of UPR^mt in trauma and critical illness. Moderate activation promotes mitochondrial recovery, limits reactive oxygen species accumulation, and supports immune cell function, thereby enhancing tissue resilience and repair. In contrast, sustained or dysregulated UPR^mt contributes to mitochondrial failure, sterile inflammation, and the progression to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). Furthermore, we discuss emerging evidence linking UPR^mt to immune regulation and inflammatory responses, and propose that targeting key regulatory nodes within this stress-integration network may offer novel therapeutic strategies for a broad spectrum of human diseases. Crucially, we synthesize how UPR^mt mechanisms contribute to post-traumatic mitochondrial damage, sterile inflammation, SIRS, and MODS. We propose that targeting key regulatory nodes within this stress-integration network may offer novel therapeutic strategies for trauma, burns, and critical illness.

Background: Sepsis-related myocardial dysfunction significantly increases the mortality risk of sepsis. However, its underlying mechanism remains incompletely understood, and effective therapeutic strategies are still lacking. Transcriptomic profiling from septic patients showed endoplasmic reticulum stress (ERS) were the main pathways participating in the occurrence of sepsis myocardial dysfunction. Therefore, this study aimed to explore the protective effect of 4-phenylbutyric acid (4-PBA) on sepsis-induced myocardial injury and specify its molecular regulatory mechanism, to provide experimental basis for clinical intervention of septic myocardial dysfunction. Methods: In vivo and in vitro models of sepsis were used, and 4-PBA (5 mg/kg) was administered for intervention. Mitochondria-associated ER-membrane (MAM) formation, mitochondrial dynamics, mitochondrial function, glycolytic metabolism, and protein lactylation were systematically examined. Molecular docking and site-directed mutation were applied to verify the direct binding and catalytic sites of 4-PBA. Results: 4-PBA significantly alleviated sepsis-induced myocardial dysfunction (SIMD). The mechanism was closely related to 4-PBA inhibiting MAM formation and improving the mitochondrial dynamic balance and mitochondrial function. 4-PBA inhibited MAM formation mainly via decreasing the lactate production and lactylation of Arpc1b-K308 by inhibiting the glycolysis limiting enzyme HK2, and 4-PBA inhibited HK2 activity by binding K621 and K624 catalytic sites. Conclusions: The results indicate that 4-PBA protects cardiac function following sepsis by recovering mitochondrial dynamics balance. This finding provides a novel therapeutic strategy and potential target for SIMD.

Background: Hypertrophic scars are a major clinical challenge with limited treatments. Adipose-derived stem cells (ADSCs) play an important role in inhibiting pathological scar formation. However, the underlying mechanisms remain unclear. In this study, we aimed to investigate the function, mechanism, and therapeutic potential of adipose-derived stem cell peptide 5 (ADSCP5), a novel peptide from adipose-derived stem cell-conditioned medium. Methods: We used in vitro hypertrophic scar fibroblast, macrophage–fibroblast coculture and human umbilical vein endothelial cell (HUVEC) assays, RNA sequencing, pathway analysis, peptide pull-down, molecular docking, cellular thermal shift assays, surface plasmon resonance, immunofluorescence colocalization analysis, western blotting, rescue experiments, reactive oxygen species (ROS), autophagy tests, and mitochondrial membrane potential assays and untargeted metabolomics. The efficacy of ADSCP5 was validated in rabbit and porcine scar models. Results: In hypertrophic scar fibroblasts, ADSCP5 significantly downregulated the expression of collagen genes (COL1A1, COL1A2, and COL3A1) and actin alpha 2, smooth muscle, without affecting cell proliferation, apoptosis, or migration. Transcriptomic, enrichment, and western blot analyses confirmed that ADSCP5 reduced the protein levels of phosphorylated p65 (p-p65, NF-κB subunit), p-PI3K, p-AKT, and p-mTOR. Moreover, ADSCP5 decreased IL-6 transcription. Mechanistically, ADSCP5 bound directly to pyruvate carboxylase or the NF-κB subunit p50. This interaction resulted in the downregulation of PC or the upregulation of p50, ultimately inhibiting collagen expression, a finding confirmed by rescue assays. Furthermore, ADSCP5 induced ROS generation and autophagy, altered global metabolism, and modulated macrophage–fibroblast crosstalk to suppress fibrosis. It also exhibited antiangiogenic effects in HUVECs. In both the rabbit and porcine scar models, ADSCP5 treatment effectively attenuated collagen deposition and scar hyperplasia, increased the number of macrophages (increased CD68), reduced angiogenesis (decreased VEGFA and CD34), and promoted autophagy (reduced p62). Conclusions: Overall, this study demonstrate that ADSCP5 alleviates hypertrophic scarring by directly binding to PC and p50, suppressing the PI3K/AKT/mTOR and NF-κB pathways, reducing IL-6 and collagen production, promoting ROS and autophagy, and modulating metabolic, macrophage and angiogenic responses. These findings position ADSCP5 as a promising therapeutic agent for hypertrophic scar prevention and treatment.

Diabetic wound healing is a common yet challenging problem in clinical practice that involves complex pathophysiological processes and frequently progresses to chronic nonhealing wounds, imposing substantial burdens on both healthcare systems and patients while markedly decreasing quality of life. Persistent inflammatory responses represent a fundamental pathological feature of this condition. Accumulating evidence highlights the key role of neutrophil extracellular traps (NETs) in the chronic inflammatory response characteristic of diabetic wounds. As components of the innate immune system, NETs play pivotal roles in both host defence and tissue repair. Neutrophil extracellular trap formation (NETosis) is currently classified as vital NETosis or lytic NETosis. In this review, we synthesize existing evidence on the mechanistic heterogeneity of NETosis and further refine lytic NETosis subtypes on the basis of distinct molecular mechanisms and temporal dynamics-namely, NADPH oxidase 2 (NOX2)-dependent classical lytic NETosis and mitochondrial reactive oxygen species–driven rapid lytic NETosis. We also highlight the functional outcomes of NETs in response to specific stimuli within the diabetic wound milieu. Therapeutic strategies targeting NET formation, degradation, or neutralization have shown considerable promise in preclinical studies; however, their clinical translation will require standardized biomarkers for NET quantification, localized delivery approaches to minimize systemic immunosuppression, and biomarker-guided frameworks to balance the risk of infection against healing benefits.

Background: Diabetic foot ulcers (DFUs) are severe complications of diabetes, and treatment options for DFUs are limited. Current research on impaired angiogenesis in DFUs predominantly relies on generic endothelial cells, which inadequately reflect the pathophysiological microenvironment of the diabetic microvasculature. In contrast, this study focused specifically on human dermal microvascular endothelial cell (HDMEC) senescence as a central mechanism in DFU progression. We used a self-feeder layer 3D (SFL-3D) culture system to reprogram adipose-derived mesenchymal stem cells (ADSCs) to prepare functionally enhanced three-dimensional adipose stem cells (tdASCs) and their extracellular vesicles (tdASC-EVs) to mitigate HDMEC senescence and improve diabetic healing. Methods: EVs were isolated from SFL-3D-induced tdASCs and characterized. In vitro, high-glucose-induced HDMECs were treated with tdASC-EVs, after which senescence, oxidative stress, mitochondrial function, and angiogenesis were assessed. Pathway-specific inhibitors and a phosphorylation-mimetic 4EBP1 plasmid were used to validate the mechanistic involvement of the phosphatidylinositol 3-kinase/Ak strain transforming/mechanistic target of rapamycin/4E-binding protein 1 (PI3K/AKT/mTOR/4EBP1) axis and cap-dependent translation via m⁷GTP pull-down. In vivo, a fat graft model was used to assess the stem cell function of tdASCs, whereas a diabetic wound model was used to evaluate the therapeutic efficacy of tdASC-EVs. Results: tdASC-EVs significantly attenuated high-glucose-induced HDMEC senescence, oxidative stress, and mitochondrial dysfunction while increasing tube formation. Mechanistically, tdASC-EVs activated PI3K/AKT/mTOR signaling, increased 4EBP1 phosphorylation, and promoted eIF4E–eIF4G assembly. In diabetic mice, tdASC-EVs accelerated wound closure and increased microvascular density, which correlated with reduced p16 expression and increased CD31 and p-4EBP1 expression. In the Bama miniature pig diabetic large animal model, tdASC-EVs exhibited markedly superior therapeutic effects compared with those induced by conventional ADSC-EVs, as evidenced by significantly faster wound closure, greater neovascularization density, narrower scar width, and more orderly collagen deposition. Conclusions: tdASC-EVs ameliorated diabetic wound healing by targeting HDMEC senescence through PI3K/AKT/mTOR/4EBP1-mediated cap-dependent translational activation. The preclinical large animal data further confirmed the superior efficacy of tdASC-EVs over ADSC-EVs, highlighting the therapeutic potential of SFL-3D-modified EVs for DFU treatment.

Mitochondria not only serve as cellular powerhouses and metabolic regulatory hubs but also play crucial roles in calcium homeostasis, apoptosis regulation, and signal transduction. During wound repair, mitochondria modulate inflammatory and immune responses; drive angiogenesis; and supply energy for the proliferation, differentiation, and migration of repair cells such as fibroblasts and epithelial cells. When mitochondrial dysfunction exceeds the self-regulatory capacity, cellular energy deficits, metabolic disturbances, dysregulated signaling, and oxidative stress damage occur. These abnormalities collectively impair cellular repair mechanisms, ultimately contributing to chronic nonhealing wounds. Historically, mitochondria were thought to be acquired via vertical inheritance through cell division or mitochondrial biogenesis. However, the discovery of intercellular mitochondrial transfer provides novel insights into mitochondrial acquisition and presents new avenues for rescuing mitochondrial dysfunction. This article comprehensively reviews the dialectical relationship between mitochondrial dysfunction and impaired wound healing by integrating mechanisms of mitochondrial transfer, including modes, triggers, and regulatory pathways. It further highlights the therapeutic potential of mitochondrial transfer in wound repair. Additionally, this article provides forward-looking perspectives on clinical applications and future developments in mitochondrial transfer for wound healing, aiming to establish a theoretical foundation for mitochondrial transplantation therapies.

The stagnation of diabetic wound healing is a formidable global health challenge that is fundamentally driven by the dysregulation of macrophage plasticity. In the diabetic microenvironment, macrophages remain in a persistent pro-inflammatory (M1) state and fail to transition to the reparative (M2) phenotype essential for tissue regeneration. This review systematically elucidates the molecular pathology of this ‘conversion failure’ from a superficial to an in-depth level and provides a detailed explanation of the mechanisms underlying aberrant macrophage polarization in diabetic wounds, ranging from microenvironmental abnormalities to dysregulated signalling pathways. These perturbations create a vicious cycle of chronic inflammation, impaired angiogenesis, and pathological fibrosis. To address these challenges, we comprehensively outline current therapeutic strategies, including approaches that range from the precision molecular reprogramming of intracellular signalling hubs and gene networks to the engineering of microenvironment-responsive biomaterials capable of neutralizing oxidative stress and responding to pathological cues. Furthermore, we highlight the integration of exogenous bioactivity through stem cell– and exosome-based therapies aimed at replenishing the regenerative niche. Additionally, we critically assess translational bottlenecks, suggesting a paradigm shift from the binary M1/M2 model towards targeting intermediate phenotypes identified by single-cell multiomics. By integrating mechanistic insights with advanced immunomodulatory engineering, this review provides a theoretical framework for developing next-generation precision therapies to reverse the chronic nature of diabetic wounds.

Chronic non-healing wounds, particularly diabetic foot ulcers, persist as a significant clinical challenge due to the limited availability of therapeutic options and the complexity of their pathological microenvironments. Plant-derived extracellular vesicles (PDEVs), which are nanoscale lipid carriers rich in bioactive molecules, have emerged as a promising therapeutic approach due to their low immunogenicity, antioxidant, anti-inflammatory properties, and their ability to promote angiogenesis. Structurally, the biomaterial protects the integrity of PDEVs and extends their residency through modulated release. Biologically, PDEVs enhance the regenerative potential of the material by profoundly reprogramming the local cellular and immune microenvironments. However, their clinical application is severely impeded by their inherent instability in the dynamic wound microenvironment, which includes susceptibility to enzymatic degradation, disruption due to pH fluctuations, and rapid clearance by wound exudate. These factors collectively lead to premature cargo loss and reduced therapeutic efficacy. This review synthesizes how engineered biomaterials, serving as tailored structural platforms for controlled delivery, can overcome these stability challenges specific to PDEVs. By examining loading strategies and design principles, we demonstrate how composite systems surpass single-component therapies in wound models. Lastly, we address translational challenges and propose a development framework that integrates artificial intelligence–driven design with mechanism-guided material optimization. This work lays the groundwork for the rational development of next-generation vesicle-enabled wound therapeutics.

Background: Diabetic foot ulcers remain a major clinical challenge, driven by the convergent effects of microbial infection, chronic inflammation, oxidative stress, and inadequate neovascularization that collectively disrupt tissue repair. Although the integrin α v β3 agonist peptide FZ1 exhibits promising pro-healing activity, limited delivery control and insufficient functional versatility have restricted its clinical translation. To overcome these constraints, a pH-responsive hyaluronic acid (HA)-based hydrogel, hyaluronic acid conjugated with FZ1 peptide (HA-c-FZ1), was developed to enable intelligent acidity-triggered peptide release while integrating antimicrobial activity, reactive oxygen species (ROS) scavenging, and inflammation control within a single wound dressing platform for diabetic wound repair. Methods: Photo-crosslinkable oxidized methacrylated HA was synthesized and covalently linked to FZ1 through a pH-labile Schiff base bond, yielding HA-c-FZ1 hydrogel at three concentrations (2%, 3%, and 4%). HA-c-FZ1 hydrogel morphology, swelling behavior, mechanical properties, peptide-loading efficiency, pH-responsive release, antioxidant activity, antibacterial activity, biocompatibility, and anti-inflammatory effects were systematically evaluated in vitro. Therapeutic efficacy was then assessed in a diabetic mouse model with infected full-thickness skin wounds through wound closure analysis, histological staining, immunofluorescence detection of macrophage polarization markers (inducible nitric oxide synthase and arginase) and angiogenic markers (alpha-smooth muscle actin and vascular endothelial growth factor), and laser speckle imaging of blood perfusion. Transcriptomic profiling, RT-qPCR, and western blotting were performed to define the molecular mechanisms underlying HA-c-FZ1-mediated wound repair. Results: HA-c-FZ1 hydrogel formed a homogeneous porous hydrogel network with predictable swelling behavior, tunable mechanical performance, high FZ1 loading efficiency, and accelerated peptide release under acidic conditions. In vitro, HA-c-FZ1 hydrogel promoted keratinocyte proliferation and migration, reduced ROS accumulation, and inhibited Staphylococcus aureus and Escherichia coli survival. In infected diabetic wounds, HA-c-FZ1 hydrogel suppressed bacterial burden and accelerated wound closure, accompanied by enhanced re-epithelialization, collagen deposition, angiogenesis, and local blood perfusion. Mechanistic analyses indicated that HA-c-FZ1 hydrogel attenuated nuclear factor kappa B-associated inflammatory signaling, promoted M2 macrophage polarization, and activated focal adhesion kinase–protein kinase B-dependent angiogenic responses. Conclusions: HA-c-FZ1 functions as a pH-responsive hydrogel dressing that combines peptide delivery with antimicrobial, redox-regulatory, immunomodulatory, and pro-angiogenic functions. These findings position it as a therapy for chronic diabetic wound repair by simultaneously addressing infection, inflammation, oxidative stress, and vascular regeneration.

Background: Spinal cord injury (SCI) is a severe traumatic condition with limited treatments. Ferroptosis, an iron-dependent type of controlled cell death, participates in SCI pathology. Nonetheless, the molecular mechanisms governing ferroptosis after SCI remain incompletely understood. Therefore, this study aims to elucidate the regulatory role of SIRT6 in neuronal ferroptosis post-SCI, identify its upstream modulator and downstream target, and evaluate the therapeutic potential of targeting this pathway for functional recovery. Methods: Ferroptosis markers were assessed in SCI mouse models and primary neurons. Sirtuin 6 (SIRT6) expression was regulated via lentiviral vectors and adeno-associated viral vectors. Protein interactions were identified by immunoprecipitation coupled with mass spectrometry and co-immunoprecipitation. Ubiquitination assays were conducted using ubiquitin mutants. Nuclear transcription factor erythroid 2-related factor 2 knockout (NRF2-KO) mice were used for in vivo validation. Functional recovery was evaluated by Basso Mouse Scale score, rotarod test, footprint analysis, and electromyography. Results: SIRT6 expression was downregulated following SCI and during erastin-induced ferroptosis. SIRT6 overexpression inhibited ferroptosis and triggered functional recovery, while SIRT6 suppression exacerbated these effects. Mechanistically, SIRT6 interacted with and deacetylated NRF2, promoting its nuclear translocation and antioxidant gene activation. STIP1 homology and U-box containing protein 1 (STUB1) was identified as an upstream regulator that physically interacted with SIRT6 via its U-box domain. STUB1 stabilized SIRT6 by promoting K63-linked ubiquitination, protecting it from proteasomal degradation. STUB1 overexpression inhibited ferroptosis and improved functional recovery, effects that were abolished by SIRT6 knockdown or NRF2-KO. Conclusions: The STUB1/SIRT6/NRF2 axis represents a novel regulatory pathway that suppresses neuronal ferroptosis and promotes functional recovery post-SCI. Targeting this axis may offer a prospective therapeutic strategy for SCI.

Background: Autologous and allogeneic bone grafts are primarily used for bone tissue defects; however, they have limitations such as limited supply, donor site morbidity, and immune rejection risks. Therefore, substitute synthetic bone grafts are required. This study aims to develop a cryogenic 3D-printed PLGA/HA@SeNPs scaffold that synergistically regulates macrophage polarization and osteogenic differentiation for bone regeneration. Methods: Using low-temperature 3D printing combined with freeze-drying technology, a hierarchically porous PLGA/HA@SeNPs composite scaffold was fabricated by compositing poly(lactic-co-glycolic acid) (PLGA) with hyaluronic acid-modified selenium (Se) nanoparticles (HA@SeNPs), enabling sustained immunomodulation and osteogenic activity through its engineered microtopography and bioactive components. Results: In vitro evaluations confirmed that the unique microstructure and sustained Se release from HA@SeNPs synergistically promoted macrophage polarization toward the M2 phenotype, accompanied by enhanced osteogenic differentiation as shown by upregulation of Runx2 and osteocalcin and accelerated matrix mineralization. Implantation into a rat femoral critical-sized defect model resulted in substantially improved bone repair and architectural restoration. Conclusions: These findings indicate that the intrinsic physicochemical properties of the PLGA/HA@SeNPs scaffold orchestrate a favorable osteo-immune environment, positioning it as a promising platform for bone regeneration.

Pathological scars (PSs) are characterized by excess dermal collagen deposition and primarily manifest as hypertrophic scars and keloids. The microenvironment of PSs is shaped by a diverse array of cells, collectively forming a profibrotic and proangiogenic niche. Recent advances in high-throughput sequencing have enhanced our understanding of the cellular heterogeneity, transcriptional changes, and intercellular communication within the PS microenvironment. This review comprehensively describes the cellular landscape of PSs, including mesenchymal cells, endothelial cells, epithelial cells, and immune cells. Additionally, we evaluate precision medicine strategies ranging from biomarker-driven diagnostics to targeted biological therapies and innovative drug delivery systems. We aim to provide a mechanistic framework that accelerates the translation of basic experimental research into effective and personalized treatments for pathological scarring.

Background: Keloids, which are characterized by excessive collagen deposition and fibroblast hyperactivation, present significant therapeutic challenges because of their high recurrence rates and incompletely understood pathogenesis. The transforming growth factor-β (TGF-β) pathway is a central driver, but its upstream regulators in the development of skin fibrosis remain elusive. In this study, we aimed to identify novel upstream modulators of skin fibrosis and to elucidate the underlying molecular mechanisms by which these modulators regulate TGF-β signaling in keloid pathogenesis. Methods: We integrated results of transcriptomic and proteomic analyses of patient-derived keloid and normal skin tissues. Functional validation was performed by using primary keloid fibroblasts (KFs) with gain-and loss-of-function approaches, RNA immunoprecipitation sequencing (RIP-seq), and actinomycin D chase assays. Two independent bleomycin-induced skin fibrosis mouse models were employed for in vivo validation. Results: Multiomics profiling revealed that caveolae-associated protein 1 (CAVIN1) was consistently downregulated in keloids. CAVIN1 overexpression in KFs suppressed fibrotic phenotypes, including migration, invasion, collagen contraction, and extracellular matrix protein expression. Mechanistically, CAVIN1 directly bound to and stabilized the mitochondrial long noncoding RNA GAS5. This CAVIN1/GAS5 axis inhibited Drp1/Fis1-mediated mitochondrial fission and subsequent reactive oxygen species (ROS) production, leading to the attenuation of the canonical TGF-β/Smad2/3 signaling pathway. Critically, GAS5 silencing abrogated the antifibrotic effects of CAVIN1. Furthermore, database screening revealed that the histone deacetylase inhibitor vorinostat was a CAVIN1-upregulating compound. Both AAV-mediated CAVIN1 overexpression and vorinostat treatment significantly ameliorated skin fibrosis in the mouse models. Conclusions: Our study reports a novel CAVIN1/GAS5 axis that concurrently targets mitochondrial fission and the TGF-β/Smad pathway to suppress skin fibrosis. These findings not only reveal a previously unrecognized mechanistic link in keloid pathogenesis but also identify CAVIN1 as a promising therapeutic target, with vorinostat as a potential repurposable drug for treating fibrotic skin disorders.

Background: Axonal regeneration following spinal cord injury (SCI) is hindered by the intrinsic inhibitory properties of spinal neurons. While the role of the transcription factor SPI1 (PU.1) has been well established in myeloid cells, its function in neurons, particularly in regulating axonogenesis, remains poorly defined. The data from recent single-cell sequencing studies have indicated that SPI1 is clearly expressed in spinal neurons. Thus, we aimed to explore the effect of SPI1 on axonal growth and its underlying molecular mechanisms. Methods: Primary cultured rat spinal neurons, CRISPR/Cas9-mediated SPI1 mutation in zebrafish, and neuron-specific AAV9–shRNA delivery after rat spinal cord hemisection were utilized to manipulate SPI1 expression. RNA-seq, luciferase reporter assays, ChIP–qPCR, and Cut&Tag assays were employed to identify and validate Rassf10 as a candidate target gene of SPI1. Axonal outgrowth and functional recovery postinjury were assessed both in vitro and in vivo. Results: Neuronal SPI1 expression declined progressively during spinal cord development but was markedly upregulated after SCI. SPI1 knockdown promoted axonal outgrowth, whereas SPI1 overexpression significantly reduced the axonal length. The transcriptomic analysis revealed that Rassf10 is a target gene of SPI1, which was subsequently validated by the results of luciferase reporter, ChIP–qPCR, and Cut&Tag assays. In vivo, spi1 mutation in zebrafish and neuron-specific SPI1 knockdown in rats facilitated axonal regeneration and functional recovery after SCI, as evidenced by significant increases in GAP43, NF200, and 5-HT expression and improved motor function compared with the control animals. The depletion of SPI1 or Rassf10 increased p-p38 mitogen-activated protein kinase levels and promoted axonal growth, whereas p38 inhibition abrogated these effects. Conclusions: SPI1 impairs axonal growth and regrowth by transcriptionally activating Rassf10 expression, with this inhibitory effect mediated by the suppression of p38 MAPK signaling. These findings suggest that targeting the SPI1–Rassf10 pathway represents a promising therapeutic strategy for improving neural repair after SCI.

Chronic wounds represent a major and growing clinical burden, particularly among aging populations and individuals with diabetes, in whom persistent inflammation and immune dysregulation delay normal tissue repair. Addressing this challenge requires functional materials that do more than passively cover the wound and instead actively regulate the wound microenvironment. Advances in hydrogel chemistry and bioengineering have enabled the development of bioadhesive interfaces that maintain stable contact with wound tissue while modulating immune and regenerative responses. In this Review, we present bioadhesive hydrogels as immunomodulatory interfaces rather than simple wound coverings and systematically examine their mechanisms of action, including the reduction of microbial and inflammatory stimuli; modulation of macrophage polarization; regulation of NF-κB-, NLRP3-, and STAT-associated signaling; and control of mechanobiological signaling at the material–tissue interface. Through these mechanisms, bioadhesive hydrogels can alleviate excessive inflammation and support a regenerative microenvironment that promotes angiogenesis, re-epithelialization, and extracellular matrix remodeling. We classify the engineering approaches used to achieve these functions into four complementary strategies. Structural and protective hydrogels stabilize the wound and protect it from contamination and mechanical disruption. Bioactive and regenerative systems deliver therapeutic molecules or cells to regulate inflammation and promote repair. Externally activated platforms provide spatiotemporal control over therapeutic activity, whereas sensing-integrated systems monitor wound conditions and support adaptive or closed-loop treatment. We also discuss major translational barriers, including unstable adhesion under exudative and mechanically dynamic conditions, limited long-term safety data, insufficient standardization, manufacturing challenges, and unclear regulatory pathways. Future progress will require disease-specific material design, clinically relevant validation, and the reliable integration of sensing and therapeutic functions.

Background: Autologous fat grafting is widely used in reconstructive and esthetic surgery, but its clinical outcomes are limited by early ischemia–hypoxia, oxidative stress, delayed vascularization, and subsequent lipid accumulation-induced inflammation. Current therapeutic strategies generally focus on single-stage regulation and lack temporal coordination with the dynamic pathological evolution of transplanted adipose tissue. Here, we developed a root system-inspired core–shell microneedle (MN) platform capable of sequentially regulating the graft microenvironment through early vascular promotion and later lipid removal. Methods: Vascular endothelial growth factor-loaded modified silk fibroin methacryloyl/grooved poly(lactic-co-glycolic acid) core–shell MNs (VEGF@mSF/gPLGA–MNs) were fabricated by integrating a reactive oxygen species (ROS)-responsive mSF shell with a lipid-adsorbing gPLGA core. The physicochemical properties, ROS scavenging ability, VEGF release behavior, and lipid adsorption capacity of the MNs were systematically characterized. Their biological effects were evaluated using in vitro cellular assays and a mouse autologous fat grafting model. Graft survival, vascularization, inflammatory regulation, and adipose remodeling and the underlying molecular mechanisms were assessed by imaging, histological analyses, immunofluorescence staining, ribonucleic acid sequencing, and western blotting. Results: The mSF shell rapidly responded to oxidative stress and degraded during the early stage after implantation, enabling localized VEGF release while alleviating ROS-induced cellular damage. Following shell degradation, the exposed gPLGA core facilitated directional lipid adsorption owing to its lipophilic properties and groove-mediated capillary transport. In vitro studies demonstrated improved endothelial migration, angiogenesis, ROS clearance, and mitochondrial protection. In a mouse fat graft model, VEGF@mSF/gPLGA–MNs significantly improved graft retention, reduced cystic degeneration and fibrosis, increased vascularization, and promoted adipose tissue remodeling. Transcriptomic and protein analyses revealed that lipid metabolism-related pathways, including PPAR signaling, were activated, and that inflammatory pathways, such as the NF-κB, TNF, IL-17, and toll-like receptor signaling pathways, were suppressed. Conclusions: The root system-inspired VEGF@mSF/gPLGA–MN platform enables spatiotemporally sequential regulation of the fat graft microenvironment by coordinating early vascular reconstruction with subsequent lipid clearance. This strategy provides a promising approach for improving fat graft survival and may offer a generalizable paradigm for regenerative therapies involving dynamic pathological transitions.

Spinal cord injury (SCI) remains a major clinical challenge due to its limited therapeutic options and the resulting severe functional impairments. Autophagy is an essential intracellular degradation process that plays a critical role in maintaining cellular homeostasis by degrading and recycling abnormal proteins and toxic substances. Recent studies have shown that autophagy significantly regulates several key pathological processes in the acute phase of SCI, including oxidative stress and neuroinflammation, and may also influence axonal regeneration during subsequent repair stages. Pharmacological modulation of autophagic flux has shown therapeutic promise and may exert neuroprotective effects. However, the precise relationship between autophagy activation or inhibition and functional recovery remains controversial and has not been fully elucidated. This review systematically summarizes recent advances in understanding the role and regulatory mechanisms of autophagy in the pathological processes of SCI, with particular emphasis on current controversies and unresolved issues. It also outlines potential pharmacological strategies targeting autophagy and proposes future research directions to support the clinical translation of these therapeutic approaches.

Background: Intestinal barrier failure following ischemia–reperfusion (IR) injury is a critical event that drives lethal systemic complications; however, the specific intercellular signals governing epithelial cell fate under these pathological conditions remain incompletely understood. Methods: We performed single-cell ribonucleic acid sequencing (scRNA-seq) on intestinal tissues from a murine IR model to map intercellular communication networks. The identified ligand–receptor pair was functionally validated using neutrophil-specific thrombospondin-1 (Thbs1) knockout mice, combined with pharmacological inhibition and activation of CD36, as well as biochemical and histological analyses. Results: scRNA-seq analysis of the IR-injured gut revealed a key neutrophil–epithelial signaling pathway mediated by the Thbs1–Cd36 ligand–receptor pair. Neutrophil-specific genetic ablation of Thbs1 markedly attenuated IR-induced epithelial apoptosis and barrier disruption. Mechanistically, THBS1 binding to epithelial CD36 activated JNK signaling, mediating a proapoptotic cascade. CD36 inhibition was protective, whereas its activation bypassed the requirement for THBS1 and provoked mucosal injury. Conclusions: Our study elucidates a key mechanism of gut barrier failure and identifies the THBS1–CD36–JNK axis as a promising therapeutic target for mitigating intestinal IR injury in critical conditions such as burns and shock.

Viable microalgal cells have recently emerged as promising photosynthetic components of advanced wound healing systems because they can combine light-regulated oxygen generation, bioactive metabolite production, intrinsic imaging potential, and engineering flexibility within a single platform. In wounds with impaired or threatened healing such as burn wounds, traumatic full-thickness wounds, infected wounds, and chronic diabetic wounds, hypoxia, excessive inflammation, microbial burden, and impaired angiogenesis collectively hinder tissue repair and limit the efficacy of the currently employed therapies. In this review, the mechanistic basis and translational potential of microalgae in wound care is examined, with a focus on photosynthesis-driven oxygenation, antimicrobial and anti-inflammatory activities, antioxidant effects, immunomodulation, and bioimaging capability. We further summarize how viable microalgal cells or cell-derived products have been incorporated into hydrogels, 3D-bioprinted scaffolds, microneedles, electrospun matrices, coatings, and other biohybrid systems to achieve localized oxygen delivery, therapeutic molecule release, and multifunctional wound intervention. Importantly, we discuss the wound type–specific suitability of different microalgae-based platforms and critically compare them with existing oxygenation and antimicrobial strategies. We also highlight key barriers to clinical translation, including immune-mediated clearance, uncertain long-term survival and photosynthetic persistence in hostile wound microenvironments, limited light penetration, biosafety concerns, and challenges in manufacturing and standardization. Overall, microalgae-based wound therapeutics represent a highly promising but still early-stage strategy, and future progress will depend on mechanism-driven design, rigorous in vivo validation, and clinically relevant translational frameworks.