Cancer is one of the most complex diseases and the second leading cause of mortality worldwide. Due to its poor prognosis and challenges in diagnosis, eradicating cancer remains highly difficult. The limitations associated with conventional therapies have led to the emergence of copious therapeutic strategies such as chemotherapy, phototherapy, starvation therapy, radiotherapy and immunotherapy; however, limited therapeutic efficacy, poor tumor cell selectivity and substantial adverse effects remain significant concern. Attributed to the expeditious advancement of nanotechnology, the amalgamation of nanomaterials with therapeutic approaches provides an opportunity to address the shortcomings of conventional chemotherapy. Metal-organic frameworks (MOFs), which consist of bridging ligands and ions/clusters connected by coordination bonds, have been widely used in cancer therapy to address the limitations of currently therapeutic interventions, such as poor efficacy, low stability and severe side effects. This potential arises from their tuneable porosities, high specific surface area-to-volume ratio, tailorable diameters, tractable morphologies, variegated compositions, biocompatibility and facile functionalization. We summarized the role of MOF-based nanoplatforms along with mechanistic insights into emerging avenues-such as cuproptosis, ferroptosis, cellpenetrating and biomimetic MOFs, and tumor microenvironment-responsive MOFsalongside recent advancements in mono- and multifunctional cancer therapeutics. Theragnostic and imaging functionalities, as well as regulatory considerations and future prospects of MOF-based nanoplatforms utilized in cancer treatment, are also discussed.
Psoriasis is a chronic inflammatory skin disease, which seriously affects the physical and mental health of patients. The progression of psoriasis is influenced by the excessive production of reactive oxygen species (ROS) and inflammatory responses. In this paper, novel celastrol (Ce)-loaded metal-phenolic nanozymes (tannic acid-Fe 3+ ) (TA-Fe) integrated microneedles (Ce@TA-Fe/MNs) were constructed to achieve the combined oxidative stress alleviation and anti-inflammatory therapy of psoriasis. Molecular dynamics simulations and structural characterization confirmed the successful fabrication of nanozymes. The Ce@TA-Fe/MNs system, characterized by its rapid dissolution kinetics and superior mechanical strength, enabled minimally invasive skin penetration for efficient nanozymes delivery. Nanozymes possessed superoxide dismutase and catalase mimetic enzyme activities, effectively eliminating excessive ROS in psoriatic skin lesions. Additionally, the release of Ce from
Macrophages are critical phagocytes in the immune system, and tumor-infiltrating macrophages can substantially influence the efficacy and prognosis of immunotherapy. Therefore, macrophages may serve as therapeutic targets for modulating the tumor immune microenvironment. Macrophage-based drug delivery systems have been extensively evaluated owing to their excellent biocompatibility, long half-life, and inherent ability to migrate and accumulate at sites of inflammation, such as tumors. Live macrophages and their membrane coatings contain abundant receptor proteins that facilitate payload transport across physiological barriers. In this review, we discuss strategies that utilize macrophages as targets and delivery carriers for cancer immunotherapy. Here, we summarize the different macrophage phenotypes, tumor-associated macrophagetargeting strategies, and biomimetic delivery carriers derived from macrophages used in immunotherapy. Overall, macrophage-centered strategies for cancer therapy hold considerable promise for clinical applications.
Immunotherapy of triple-negative breast cancer (TNBC) is significantly hindered by the immunosuppressive tumor microenvironment (TME). Notably, tumor-associated macrophages (TAMs), which constitute the predominant infiltrating immune cell type in TNBC, represent a critical target for "turning off" immunosuppressive TME. Despite numerous ongoing clinical trials, current strategies exhibit limited efficacy in overcoming immunosuppressive TME. Interestingly, regulation of son of sevenless 1 (SOS1), which is overexpressed in TNBC patients, shows promising potential for TAM repolarization. Herein, we developed a biomimetic liposomal platform (CCM/Cil-lipo@TD), which integrates cilengitide (Cil)-functionalized breast cancer cell membranes (CCM) to co-deliver tetrandrine (TET) and low-dose docetaxel (DTX) for TNBC therapy. This system synergistically enhanced immunotherapy by coupling SOS1 blockade-driven TAM repolarization with immune cell death (ICD)-mediated dendritic cell (DC) maturation, thereby reshaping the highly immunosuppressive TME in TNBC. Critically, the low-density Cil-anchored, CCM-fused liposomes overcome the penetration limitations inherent to conventional CCM-based delivery systems, achieving deep intratumoral accumulation of therapeutic payloads. Mechanistically, the CCM/Cil-lipo@TD ensured that TET-mediated SOS1 inhibition in tumor cells efficiently polarized TAM2 (protumor) toward TAM1 (antitumor). Furthermore, SOS1 blockade synergized with low-dose DTX-induced ICD to remodel TME, as evidenced by sustained cytotoxic T-cell infiltration and suppression of regulatory T cells. The CCM/Cil-lipo@TD exerted superior tumor inhibition (82.9%) in 4T1 orthotopic models and effectively inhibited postoperative local recurrence and distant metastasis. Taken together, the Cil-engineered, cell membrane-anchoring CCM/Cil-lipo@TD provides a promising approach for TNBC immunotherapy.
Cancer is a major global concern due to its high mortality rate. Tumor immunotherapy has revolutionized cancer treatment. However, low response rates and immune-related complications remain challenges. Extracellular vesicles (EVs), including exosomes, have emerged as promising therapeutic tools for various pathological conditions, especially cancer. Evidence indicates that changes in the quantity and composition of EVs can influence the immunosuppressive tumor microenvironment, potentially affecting the effectiveness of immunotherapy. Exploiting EVs for immune sensitization has generated significant clinical interest. This review provides an in-depth understanding of the origin of EVs, their therapeutic applications (such as drug delivery nanoplatforms and cancer immunotherapies, including vaccines), diagnostic potential as tumor biomarkers, ongoing EV-based clinical trials, and the challenges encountered in EV-based cancer immunotherapy.
Covalent organic frameworks (COFs) are crystalline and porous materials formed from periodically organized organic molecules bonded covalently to create highly stable architectures. Their mechanical properties can be precisely adjusted through structural modifications, making COFs exceptionally suitable for applications in cancer treatment and drug delivery. This review summarizes strategies for controlling the mechanical properties of COFs, including adjustments in structural dimensions, pore sizes and host-guest interactions. The remarkable advancements in drug delivery, cancer therapy, photodynamic therapy and photothermal therapy achieved through COFs with tunable mechanical properties are then discussed. By providing deeper insights into the biomedical applications of COF systems, this review aims to foster interdisciplinary research combining nanomedicine and COF materials. Additionally, the review explores recent studies and discoveries on COFs' potential as innovative drug carriers capable of biological overcoming barriers such as the blood-brain barrier, nasal mucosa, cutaneous layers and oral mucosa. Greater insight into both the limitations and potential of COFs could pave the way for developing more effective and targeted strategies within this challenging field.
Inflammatory skin disorders (ISDs), characterized by severe inflammation and impaired skin barrier functions, often requires persistent treatment due to chronic and relapsing natures. To address these issues, we developed a small-molecular self-assembled nanodrug (ECN) that is composed of natural epigallocatechin-3-gallate (EGCG) self-assembled with tripeptide collagen (CTP). By formulating a transdermal enhancer (cationic dendrimer) with ECN, the resulted dendrimers/ECN nanocomplex (DECN) can effectively penetrate into the skin layer, resulting in effective anti-inflammatory response and repair of skin-barrier functions. In animal models of ISDs, including atopic dermatitis (AD) and psoriasis, DECN showed remarkable skin penetration, with high level of drug deposition in the epidermal-dermal layer. By using a commercially available spray pump, DECN nanoparticles can be further translated into a spray formulation, which contributes to alleviating visible symptoms, skin lesions, and inflammatory progression of psoriasis and AD. This all-in-one spray nano-formulation offers an effective, safe, and convenient way for ISDs treatment.
Posaconazole (PCZ) is a broad-spectrum anti-fungal drug approved by FDA and currently used off-label for the treatment of fungal keratitis (FK). Although ocular route serves as the most bioavailable route for treating FK, delivery of PCZ to the eye remains a challenge due to poor permeation though the cornea and rapid elimination from the eye. Here we outline a comprehensive formulation development process, beginning with in silico studies, progressing through in vitro evaluations, and ultimately achieving therapeutic benefits in vivo. We report modified niosome-like surfactant vesicles, hereafter termed as NioTherms, formulated using a novel and simple heat-mix method, encapsulating PCZ for ocular administration in the form of an in situ gel. Excipient screening performed using in silico simulations highly correlate with in vitro studies (
Ischemic stroke is currently the second leading cause of death worldwide, and insufficient endogenous neurogenesis is the greatest cause of post-stroke disability. MicroRNAs have been proven to hold therapeutic potential, unfortunately, they have a low stability that hinders their clinical usage. Our earlier work revealed that Panax notoginseng derived exosome like nanoparticles, namely PDNs have potential to bypass BBB and reduce the cerebral ischemia/reperfusion (CI/R) damage. In this study, we employed microRNA-124 as a model therapeutic gene, utilizing its engineered variant Agomir-124 (Ago124) to optimize loading efficiency. The therapeutic effects of Ago124@R-PDN were further assessed in several sets of experiments. Pharmacokinetic study showed that erythrocyte membrane extended the half-life of PDNs from 7 min to 11.3 h, and the loading efficiency of Ago124 reached 40%. In an in vitro oxygen-glucose deprivation/reperfusion (OGD/R) model, Ago124@R-PDN enhanced IL-10 production in microglia by 67% (vs 11.7% with free Ago124), and promoted Tuj1+ neuronal differentiation by 2.23-fold compared with vehicle. Also, Ago124@R-PDN brought gene cargo into the brain, alleviated infarct volume, and improved functional behaviors in model mice. At last, we demonstrated that surface glycosyl of PDN facilitated its brain-entering ability by being recognized by sodium-glucose linked transporter-1 protein. In conclusion, our erythrocyte fused PDNs offer a promising strategy for delivering biomacromolecule to treat brain diseases.
The high mortality and disability rates associated with spontaneous intracerebral hemorrhage (sICH) are primarily attributed to secondary injuries caused by hematoma expansion from continuous bleeding or rehemorrhage. Rapid hemostasis to prevent hematoma progression is critical in clinical emergencies for improving surgical outcomes and patient prognosis. For internal hemorrhages inaccessible to external interventions, especially for sICH, intravenous hemostatic strategies are essential regardless of ultimate surgical eligibility. This study reported a stealth hemostatic anchor system based on peptide-drug conjugates. Tranexamic acid (TXA), a clinically approved antifibrinolytic agent, served as the hemostatic component, while a von Willebrand factor (vMF)-binding peptide (VBP) enabled targeted delivery by specifically binding to (vMF) exposed at vascular injury sites. A plasmin-cleavable linker was incorporated to control TXA release, ensuring site-specific drug activation. The plasmin-responsive peptide-drug conjugate (RPDC) was synthesized by covalently linking TXA to VBP via the plasmin-cleavable linker. In vitro and in vivo experiments verified the targeted hemostatic efficacy of RPDC, especially demonstrating 42% reduction in hematoma volume (P < 0.001 vs. saline; P < 0.05 vs. free TXA) with mitigated peri-hematomal pathology in the collagenase-induced ICR mouse ICH model. These results highlight the potential of the stealth hemostatic anchor as a precision therapeutic strategy for managing sICH, particularly in cases of internal hemorrhages inaccessible to surgical intervention or visual inspection. The plasmin-dependent targeting mechanism enables precise drug localization at cryptic hemorrhage sites, but further studies in larger animal models are needed to confirm its efficacy. This design offers a theoretical framework for advancing emergency interventions in cerebral hemorrhage and addressing challenges related to inaccessible bleeding sites.
Milk-derived extracellular vesicles (EVs) are promising for oral drug delivery, yet different loading methods exhibit distinct impacts on drug encapsulation and membrane integrity. This study demonstrated that sonication method achieved high drug encapsulation in commercial milk-derived EVs (S-CM EVs), but impaired EV structure, compromising transcytosis. Incubation method (I-CM EVs) preserved EVs delivery ability, but had low drug loading. Further proteomic and transmembrane studies showed that sonication greatly damaged membrane proteins involved in trans-epithelial transportation, especially endoplasmic reticulum-Golgi pathway. To overcome this dilemma, we generated a hybrid CM EVs (H-CM EVs) by fusing I-CM EVs and S-CM EVs. H-CM EVs demonstrated comparable drug encapsulation to S-CM EVs (56.14%), significantly higher than I-CM EVs (11.92%). Importantly, H-CM EVs could maintain efficient drug delivery capability by restoring membrane fluidity, repairing damaged proteins, and enhancing enzyme resistance of S-CM EVs. H-CM EVs exhibited excellent absorption characteristics with 1.85-fold higher of area under the curve and 2.50-fold higher of max plasma concentration than those of S-CM EVs. On type Ⅰ diabetic mice, orally delivery of insulin loaded H-CM EVs and I-CM EVs showed improved hypoglycemic effects with pharmacological availabilities of 5.15% and 5.31%, which was 1.7-fold higher than that of S-CM EVs (3.00%). This H-CM EVs platform not only achieved high drug loading and maintained functionality for effective oral delivery but also highlighted the significant translational potential for improved clinical outcomes.