Precise regulation of macrophage fate is crucial for effective management of inflammation. However, conventional biochemical strategies often suffer from limitations in safety and efficiency, necessitating the development of more effective and controllable alternatives. In this study, we develop an ultrasound-engineered cell culture device capable of delivering finely tuned ultrasonic mechanical stimulation and demonstrate for the first time that ultrasound can remotely and dynamically modulate macrophage phenotypic fate. Our results demonstrate that ultrasound stimulation not only induces flexible transitions between macrophage subtypes but also exhibits superior immunomodulatory performance in induction efficiency, dynamic responsiveness, and spatio-temporal controllability compared to classical biochemical methods. Transcriptome sequencing reveals that ultrasound directionally polarizes M2a macrophages via activation of the integrin αXβ2/TGF-β/c-Fos/IL-10 pathway. Based on the programmable dynamic control of macrophage phenotype, we propose “sequential ultrasound therapy” and combine it with metformin hydrogel with controlled-release function to construct a physicochemically coordinated “inflammatory switch and angiogenesis promotion” therapeutic platform, exhibiting superior inflammatory repair effects than single treatment for in vivo diabetic wounds and myocardial infarction models. Overall, this study not only advances the mechanistic understanding of ultrasound in tissue repair but also proposes a remote, non-invasive ultrasound immunotherapy paradigm with clinical translation potential.

Diabetic retinopathy (DR) is driven by chronic oxidative stress and mitochondrial dysfunction, yet effective, non-invasive strategies for mitochondrial quality control (MQC) that can traverse the blood–retinal barrier (BRB) remain limited. Here, we systematically develop and investigate a bioengineered nanoplatform—endothelial mitochondria-derived vesicles (EMDVs) from retinal microvascular cells. Through optimized functional extraction and membrane potential-preserving bioengineering, EMDVs retain critical mitochondrial membrane potential and adenosine triphosphate synthesis capabilities. Upon Coenzyme Q10 (CoQ10) modification, EMDVs exhibit potent antioxidant activity. Kinetic and phenotypic recovery assays demonstrate that EMDVs non-invasively penetrate the retina and efficiently deliver CoQ10 across the BRB to all retinal layers, restoring mitochondrial homeostasis and remodeling antioxidant defenses. Transcriptomic and mechanistic analyses further reveal that topical administration of EMDVs and CoQ10-engineered vesicles dynamically modulates the disease-dependent eIF2α-ATF4-CHOP-integrated stress response axis, facilitating repair and remodeling of the retinal barrier, particularly the microvasculature, in both early- and late-stage DR. Long-term in vivo safety evaluation confirms no systemic toxicity or local inflammation. This study introduces a mitochondria-derived vesicle nanoplatform with high BRB permeability and efficient MQC function, highlighting its translational potential as a dynamic, targeted therapeutic strategy for mitochondrial dysfunction-related degenerative diseases and versatile drug delivery across biological barriers.

Precision oncology strategies guided by tumor molecular profiling often target key genomic aberrations in patients. Herein, we assembled National Cancer Center–Clinical Diagnostics Knowledgebase, compiling clinical targeted sequencing data from 6935 tumor tissues and matched normal samples, along with available pathological and clinical information. Comprehensive genomic profiling was conducted to characterize tumor type-specific somatic alterations, and comparative analyses were performed across distinct cohorts. Key genomic characteristics included high-frequency alterations in TP53 (57.8%), APC (22.6%), KRAS (21.3%), and EGFR (17.5%), among which EGFR mutations were significantly enriched in lung adenocarcinoma patients. In this cohort, 70.2% of the samples harbored at least one clinically actionable genomic aberration. 14.9% of patients showed high tumor mutational burden (TMB > 10 mutations/Mb), and the TMB level was significantly higher in patients with microsatellite instability-high than in those with microsatellite stability. We also correlated next-generation sequencing (NGS) results with conventional molecular pathology assays. We found high consistency between ERBB2 focal amplification cases determined by NGS and clinically targetable ERBB2 amplification/HER2 overexpression cases. In conclusion, this study constructed a large-scale real-world genomic dataset representative of Chinese cancer patients, spanning multiple tumor types. Moreover, our findings underscore the clinical value of NGS in identifying patients with ERBB2 amplification who may potentially benefit from targeted treatments, particularly in non-small-cell lung cancer cases where NGS panel testing is prioritized.

Exosomes play a critical role in lung cancer metastasis, facilitating tumor progression through intercellular communication between cancer cells and the tumor microenvironment. These nanosized extracellular vesicles carry bioactive molecules such as proteins, nucleic acids, and lipids. These exosomes molecular cargos promote immune evasion, angiogenesis, pre-metastatic niche formation, metastasis, and drug resistance. Exosomes enrichment in body fluids has become a promising liquid biopsy biomarker tool for early cancer detection and treatment response monitoring. The current decade's exosome-based lung cancer therapeutic approach is showing promising outcomes (stem cell exosomes, dendritic cell exosomes). This approach, although it has some limitations, such as a lack of standardization of isolation protocol and heterogeneity. In this review, we explore the involvement of exosomes in lung cancer metastasis, theranostics application, clinical trials, challenges, and solutions. In the future, exosomes will become a promising platform for lung cancer theranostics.

Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction despite a preserved left ventricular ejection fraction, and visceral adipose tissue is implicated in its pathogenesis. We hypothesize that VAT-derived small extracellular vesicles (sEVs) impair coronary microcirculation in HFpEF, and that the SGLT2 inhibitor canagliflozin can mitigate this effect. Using a mouse model of HFpEF established by a high-fat diet and L-NAME, we found that these mice exhibited significant coronary microcirculation dysfunction. Isolated VAT-sEVs from HFpEF mice were shown to exacerbate cardiac microvascular endothelial cell (CMEC) apoptosis and impair coronary flow reserve. Mechanistically, miRNA sequencing identified mmu-miR-582-3p as a key mediator enriched in these sEVs, which promotes CMEC apoptosis and mitochondrial dysfunction by directly targeting and downregulating Rap1b. Treatment with canagliflozin improved cardiac function, reduced CMEC apoptosis, and was associated with the downregulation of mmu-miR-582-3p in VAT-sEVs and the subsequent upregulation of Rap1b in CMECs. Our findings demonstrate that VAT-sEVs contribute to coronary microcirculation dysfunction in HFpEF via the mmu-miR-582-3p/Rap1b signaling pathway. Furthermore, the therapeutic benefit of SGLT2 inhibition is associated with modulation of this pathway; however, this association may be secondary to overall disease improvement, and a direct causal link requires future validation.

The lymphatic system plays a pivotal role in both physiological and pathological processes. Lymphatic fluid, owing to its anatomical proximity to disease sites and rich composition of biomarkers, represents a promising source for liquid biopsy. Furthermore, emerging evidence under the revised Starling principle indicates that lymph-based liquid biopsies may offer superior diagnostic performance over blood-based counterparts in certain clinical scenarios, such as early-stage solid tumor detection. In this comprehensive review, we systematically: compare the biochemical and cellular characteristics of lymph with those of other biofluids used in liquid biopsies, evaluate the clinical potential and current limitations of lymph-based liquid biopsy, including available sampling techniques, and assess the diagnostic utility of lymph-derived biomarkers across various disease contexts. Our analysis underscores that the primary challenge hindering broader clinical adoption is the lack of minimally invasive and clinically feasible lymphatic sampling methods. To advance translational applications, key developments are urgently needed in three areas: innovative sampling techniques, stringent quality control standards, and highly sensitive and accurate detection methodologies. This review aims to emphasize the value of lymphatic biomarkers in liquid biopsy and to stimulate further research and development in this emerging field.

Organoids and organ-on-a-chips (OoCs), as innovative tools that overcome the limitations of traditional cell and animal models, provide highly biomimetic platforms for studying the pathophysiological mechanisms of the reproductive system. This review emphasizes mechanistic discoveries, disease models, and translational prospects. In contrast to previous reviews that either addressed organoids and OoCs separately or concentrated on a single organ type, this article is unique in that it (i) integrates OoC and organoid platforms for both male and female reproductive systems; (ii) identifies four cross-cutting scientific challenges (vascularization/perfusion, dynamic endocrine modeling, immune-microenvironment reconstruction, and model standardization); and (iii) highlights translational pathways, such as artificial intelligence—enabled optimization and organoid-derived extracellular vesicles. We summarize representative organoid and OoC models of key male (testis, prostate, and epididymis) and female (ovary, endometrium, and placenta) reproductive organs, and discuss prospects for multi-organ integration, personalized drug testing, and regulatory standardization. Finally, we propose prioritized technological milestones and a roadmap to expedite the clinical translation of these technologies in reproductive system research.

Drug-resistant bacterial biofilm-associated infections pose a significant threat to human health, as the physical barrier and protective matrix of biofilms enable bacterial evasion of antibiotic effects, leading to refractory infections. To address this challenge, we develop a novel photosensitizer PY and its sulfonated zwitterionic derivative PYSO₃. Both photosensitizers exhibit aggregation-induced emission (AIE) properties coupled with exceptional photodynamic and photothermal performance in aggregates. Sulfonated zwitterionic modification significantly enhance the biological activity of PYSO₃, demonstrating potent bactericidal efficacy against methicillin-resistant Staphylococcus aureus (MRSA) and mature biofilms under laser irradiation. Mechanistically, PYSO₃-mediated combinational photodynamic therapy and photothermal therapy disrupt critical bacterial survival pathways, including quorum sensing systems, glycolysis/gluconeogenesis pathways, and oxidative stress homeostasis, thereby inhibiting normal bacterial metabolism and biofilm formation. In vivo experiments reveal remarkable antibacterial performance with accelerated wound healing rates and favorable biosafety profiles. This AIE-active zwitterionic photosensitizer not only holds great promise for combating MRSA infections but also provides new design strategies for developing multifunctional antimicrobial agents targeting drug-resistant pathogens.

The gut microbiome plays a critical role in regulating the host health and disease. Metagenomics has enhanced the understanding of microbial metabolic potential through direct analysis of microbial genomes in complex environmental specimens. Microbiome-derived metabolites are key biochemical mediators in host–microbe crosstalk and have emerged as a focal point in host physiology research. They are vital for maintaining intestinal homeostasis and physiological functions and are closely associated with disease pathogenesis, particularly tumorigenesis. These metabolites, as comprehensive indicators of microbial functional status, have been utilized in oncological clinical practice for diagnosis, prognosis evaluation, and therapeutic monitoring. Here, we summarize the composition and influencing factors of gut microbiome-derived metabolites, their roles in physiological and pathological processes—with a particular focus on their association with tumorigenesis—and discuss their potential applications as biomarkers for cancer diagnosis and monitoring, as well as their therapeutic implications. This study aims to elucidate the role of gut microbiome-derived metabolites in oncogenesis and to highlight key challenges and unresolved issues within this field.

Wound healing represents a well-coordinated and sophisticated biological process characterized by the need for precise regulation and spatiotemporal synergy of multiple cells, regulatory cytokines, and signaling pathways, ultimately achieving repair and functional reconstruction of damaged tissues. In complex situations such as war, disasters and diseases, how to carry out wound management in a truly effective manner still stands as a notable challenge. The microenvironment of wound is multi-dimensional, dynamic and complex, the wound healing process is collectively regulated by endogenous biochemical signals and exogenous physical, chemical, biological factors, which makes traditional dressings often fall short of expectations in the wound healing. Stimuli-responsive hydrogels, by sensing endogenous factors (like pH, reactive oxygen species, and glucose, along with specific enzymes) or exogenous factors (light, temperature, electric fields, etc.), exhibit various intelligent characteristics, such as interacting with wounds, monitoring wound conditions or microenvironment changes, achieving precise drug release control or dynamic assessment of the wound healing process, thereby effectively promoting wound healing. Stimuli-responsive hydrogel tissue engineering strategies (scaffolds, nanofibers, microneedles, microspheres, etc.) also provide more options for wound repair. Serving as a critical overview of stimuli-responsive hydrogels, this review delves into the recent application scenarios of these hydrogels in wound management, systematically summarizes the attendant challenges, and seeks to offer a useful reference for studies in this research field.

Fluorescence imaging, serving as the primary imaging modality in modern life science research, faces a fundamental challenge in achieving high-sensitivity imaging: optimizing the signal-to-noise ratio (SNR) under dynamic and complex experimental conditions. Due to autofluorescence, shot noise, and tissue scattering, this SNR deficiency disrupts subcellular morphometry, restricts recording reliability, and ultimately propagates artifacts in subsequent analysis. This review evaluates data-driven deep learning denoising methods that overcome conventional limitations through effective feature extraction and nonlinear modeling. Focusing on fluorescence imaging acquisition under photon-limited conditions, we delineate cutting-edge architectures, including supervised learning, unsupervised learning, zero-shot learning, and hybrid approaches. By producing higher-fidelity image data, these denoising methods enhance the reliability of live-cell imaging and the accuracy of neural mechanism analysis. This advancement provides a stronger foundation for elucidating dynamic biological processes and accelerating precision medicine.

Intratumoral bacteria play vital roles in regulating tumor progression by stimulating pro-inflammatory signals or modulating the tumor microenvironment. Due to distinct characteristics, such as intrinsic targeting of tumors or inherent immunogenicity, intratumoral bacteria are capable of inducing specific tumor cell apoptosis and necrosis, or even reprogramming the tumor immune microenvironment by interacting with the immune system. Such efficacy can be further enhanced by the modifications and engineering processes, which may efficiently inhibit tumor growth with minimal side effects, thus demonstrating promising clinical translation potential. Therefore, in this review, the development and characteristics of intratumoral bacteria and their impact on tumor progression are described in detail. Moreover, the strategies and applications of these intratumoral bacteria, which are explicitly engineered to induce tumor regression through direct killing or immune modulation, are also included. Additionally, the mechanisms by which these engineered intratumoral bacteria regulate tumor progression are elucidated and discussed. More importantly, the translational significance, current challenges in clinical adaptation, and possible solutions to these challenges of engineered intratumoral bacteria are also highlighted. Overall, this comprehensive review may provide perspectives regarding the intratumoral bacteria and may offer new insights for developing novel bacteria-based therapeutic platforms against tumors.

Intercellular communication across the maternal-fetal barrier is essential for maintaining physiological balance during pregnancy. As the structural foundation of the maternal-fetal barrier, the placenta is the core site for material exchange and signaling between the mother and the fetus. Placenta-derived extracellular vesicles (PEVs), owing to their nanoscale size and lipid bilayer membrane structure, can pass through the maternal-fetal barrier via mechanisms such as endocytosis and transcytosis across the syncytiotrophoblast. Enriched in proteins, miRNAs, and lipids, PEVs contribute to immune homeostasis at the maternal-fetal interface and support fetal growth and development. They are increasingly recognized as key mediators of information exchange between the mother and the fetus. Numerous studies have indicated that in significant pregnancy complications like preeclampsia, both the concentration and cargo of PEVs undergo remarkable changes, which are closely associated with the pathological processes of pregnancy. This suggests the potential utility of PEVs as biomarkers and therapeutic targets for pregnancy-related disorders. Based on the latest research advancements, this review systematically collates the biological properties of PEVs as signal messengers and analyzes their physiological and pathological functions during pregnancy, aiming to provide new insights for research and clinical management.