Macrophages play key roles in atherosclerosis progression, and an imbalance in M1/M2 macrophages leads to unstable plaques; therefore, M1/M2 macrophage polarization-targeted treatments may serve as a new approach in the treatment of atherosclerosis. At present, there is little research on M1/M2 macrophage polarization-targeted nanotechnology. Proteolysis-targeting chimera (PROTAC) technology, a targeted protein degradation technology, mediates the degradation of target proteins and has been widely promoted in preclinical and clinical applications as a novel therapeutic modality. This review summarizes the recent studies on M1/M2 macrophage polarization-targeted nanotechnology, focusing on the mechanism and advantages of PROTACs in M1/M2 macrophage polarization as a new approach for the treatment of atherosclerosis.

In order to develop better wound dressing with excellent performance and low cost to promote wound healing at different stages, an aldehyde-terminated eight-arm PEG (8arm-PEG-CHO) was prepared and cross-linked with adenine-modified chitosan (CS-A) via a Schiff base reaction to obtain a CS-A/PEG hydrogel. The prepared CS-A/PEG hydrogel exhibited excellent self-healing, injectable and adhesion properties, strong mechanical strength, good antibacterial activities, cytocompatibility and the ROS scavenging effect. In addition, the hydrogel has the ability to promote cell migration and proliferation due to the introduction of adenine, which allows the hydrogel to promote wound healing not only during the inflammation phase, but also during the proliferation phase. The ability of the CS-A/PEG hydrogel to promote wound healing was studied in an infected wound model, and it can significantly promote the healing of infected wounds. The wounds treated with the CS-A/PEG hydrogel displayed less inflammatory cell infiltration, more angiogenesis and collagen deposition, faster regeneration of epithelial tissue. Therefore, this hydrogel can promote wound healing at the different stages, which has great application potential for use as a dressing for promoting the healing of infected wounds. An aldehyde-terminated eight-arm PEG (8arm-PEG-CHO) was prepared and cross-linked with adenine-modified chitosan (CS-A) via a Schiff base reaction to obtain a CS-A/PEG hydrogel which was developed as a wound dressing to promote wound healing.

Due to high levels of reactive oxygen species (ROS), bacterial infections, and persistent inflammatory responses, the healing of diabetic infected wounds remains challenging. Therefore, diabetic wound dressings face higher demands for antioxidant and antibacterial properties. Additionally, dressings that are injectable, self-healing, and have good adhesion are particularly ideal as they can adapt to irregular wounds and self-repair after external damage. In this study, we designed an injectable, self-healing adhesive composite hydrogel with dual functions of antibacterial and antioxidant properties by functionalizing chitosan (CS) with molybdenum disulfide (MoS2) and using the Schiff base reaction with the star-shaped eight-arm crosslinker benzaldehyde-terminated polyethylene glycol (POSS-PEG-CHO). This composite hydrogel exhibits excellent tissue adhesion, hemostatic properties, robust mechanical strength, and good cellular compatibility. The incorporation of MoS2 nanosheets (NS) endows the hydrogel with exceptional photothermal antibacterial effects and effective ROS scavenging capability. MoS2@Gel demonstrates strong ROS scavenging at the molecular level and superior antibacterial performance under near-infrared light. Moreover, in a diabetic wound infection model, MoS2@Gel significantly alleviates oxidative stress and bacterial infection during the inflammatory phase, while promoting epithelial tissue regeneration, collagen deposition, and angiogenesis, thereby accelerating the repair of diabetic wounds. Therefore, this composite hydrogel represents a promising and effective strategy for treating diabetic infected wounds.

Wound healing is a dynamic and complex process, it's urgent to develop new wound dressings with excellent performance to promote wound healing at the different stages. Here, a novel composite hydrogel dressing composed by silver nanoparticles (AgNPs) impregnated adenine-modified chitosan (CS-A) and octafunctionalized polyhedral oligomeric silsesquioxane (POSS) of benzaldehyde-terminated polyethylene glycol (POSS-PEG-CHO) solution was presented to solve the problem of wound infection. Modification of chitosan with adenine, not only can improve the water solubility of chitosan, but also introduce bioactive substances to promote cell proliferation. CS-A and POSS-PEG-CHO were cross-linked by Schiff-base reaction to form the injectable self-healing hydrogel. On this basis, AgNPs were added into the hydrogel, which endows the hydrogel with better antibacterial activity. Moreover, this kind of hydrogel exhibits excellent cell proliferation properties. Studies demonstrated that the hydrogel can significantly accelerate the closure of infected wounds. The histological analysis and immunofluorescence staining demonstrated that the wounds treated with the composite hydrogel exhibited fewer inflammatory cells, more collagen deposition and angiogenesis, faster regeneration of epithelial tissue. Above all, adenine-modified chitosan composite hydrogel with AgNPs loaded was considered as a dressing material with great application potential for promoting the healing of infected wounds.

Stem cells-derived extracellular vesicles (SC-EVs) have emerged as promising therapeutic agents for wound repair, recapitulating the biological effects of parent cells while mitigating immunogenic and tumorigenic risks. These EVs orchestrate wound healing processes, notably through modulating angiogenesis—a critical event in tissue revascularization and regeneration. This study provides a comprehensive overview of the multifaceted mechanisms underpinning the pro-angiogenic capacity of EVs from various stem cell sources within the wound microenvironment. By elucidating the molecular intricacies governing their angiogenic prowess, we aim to unravel the mechanistic repertoire underlying their remarkable potential to accelerate wound healing. Additionally, methods to enhance the angiogenic effects of SC-EVs, current limitations, and future perspectives are highlighted, emphasizing the significant potential of this rapidly advancing field in revolutionizing wound healing strategies.

Angiogenesis is essential for diabetic wound healing. Endothelial progenitor cell-derived extracellular vesicles (EPC-EVs) are known to promote wound healing by enhancing angiogenesis, while the low yield and lack of effective targeting strategies limit their therapeutic efficacy. Here, the biomimetic nanovesicles (NVs) prepared from EPC (EPC-NV) through an extrusion approach were reported, which functioned as EV mimetics to deliver contents from EPC to the wound. Besides, the cRGD peptide was coupled to the surface of EPC-NV (mEPC-NV) to achieve active endothelial cells (ECs)-targeting. Furthermore, we developed a dual hydrogel network by combining Fe3+@ Protocatechualdehyde (PA) complex-modified Acellular Dermal Matrix (ADM) with light-cured gelatin (GelMA), to enrich and sustainably release mEPC-NV. The hydrogel system with antioxidant and antibacterial properties also made up for the deficiency of mEPC-NV, reducing reactive oxygen species (ROS) and inhibiting infection in diabetic wound. Taken together, this study established a novel bioactive delivery system with angiogenesis, antioxidant and antibacterial activities, which might be a promising strategy for the treatment of diabetic wound.

Extracellular vesicles (EVs) are considered to be a new generation of bioinspired nanoscale drug delivery systems due to their low immunogenicity, natural functionality, and excellent biocompatibility. However, limitations such as low uptake efficiency, insufficient production, and inhomogeneous performance undermine their potential. To address these issues, numerous researchers have put forward various methods and applications for enhancing EV uptake in recent decades. In this review, we introduce various methods for the cellular uptake of EVs and summarize recent advances on the methods and mechanisms for enhancing EV uptake. In addition, we provide further understanding regarding enhancing EV uptake and put forward prospects and challenges for the development of EV-based therapy in the future.

Adipose-derived stem cells (ADSCs) have been widely applied in translational and regenerative medicine. During aging, there is a recognized functional decline in ADSCs, which compromises their therapeutic effectiveness. Currently, the mechanisms of aging-induced stem cell dysfunction remain unclear, hence there is a need to elucidate these mechanisms and propose strategies for reversing this functional impairment. In this study, we found that ADSCs isolated from old donors (O-ADSCs) presented inferior phenotypes and decreased miR145-5p levels compared to those from young donors (Y-ADSCs). To interrogate the role of miR-145-5p in ADSCs, gain- and loss-of-function assays were performed. The results indicated that miR-145-5p overexpression in O-ADSCs promoted cellular proliferation and migration, while reducing cell senescence. Further study demonstrated that miR-145-5p could regulate ADSCs function by targeting bone morphogenetic protein binding endothelial cell precursor-derived regulator (BMPER), which is a crucial modulator in angiogenesis. Moreover, in vivo experiments showed that miR-145-5poverexpressing O-ADSCs accelerated wound healing by promoting wound re-epithelialization and angiogenesis. Collectively, this study indicates that miR-145-5p works as a positive regulator for optimizing O-ADSCs function, and may be a novel therapeutic target for restoring aging-associated impairments in stem cell function.

Chronic skin wounds, especially infected ones, pose a significant clinical challenge due to their increasing incidence and poor outcomes. The deteriorative microenvironment in such wounds, characterized by reduced extracellular matrix, impaired angiogenesis, insufficient neurogenesis, and persistent bacterial infection, has prompted the exploration of novel therapeutic strategies. In this study, we developed an injectable multifunctional hydrogel (GEL/BG@Cu + Mg) incorporating Gelatin-Tannic acid/ N-hydroxysuccinimide functionalized polyethylene glycol and Bioactive glass doped with copper and magnesium ions to accelerate the healing of infected wounds. The GEL/BG@Cu + Mg hydrogel composite demonstrates good biocompatibility, degradability, and rapid formation of a protective barrier to stop bleeding. Synergistic bactericidal effects are achieved through the photothermal properties of BG@Cu + Mg and sustained copper ions release, with the latter further promoting angiogenesis. Furthermore, the hydrogel enhances neurogenesis by stimulating axons and Schwann cells in the wound bed through the beneficial effects of magnesium ions. Our results demonstrate that the designed novel multifunctional hydrogel holds tremendous promise for treating infected wounds and allowing regenerative neurogenesis at the wound site, which provides a viable alternative for further improving clinical outcomes.

Considerable progress has been made in the development of drug delivery systems for diabetic wounds. However, underlying drawbacks, such as low delivery efficiency and poor tissue permeability, have rarely been addressed. In this study, a multifunctional biohybrid nanorobot platform comprising an artificial unit and several biological components is constructed. The artificial unit is a magnetically driven nanorobot surface modified with antibacterial 2-hydroxypropyltrimethyl ammonium chloride chitosan, which enables the entire platform to move and has excellent tissue penetration capacity. The biological components are two-step engineered extracellular vesicles that are first loaded with mangiferin, a natural polyphenolic compound with antioxidant properties, and then glycoengineered on the surface to enhance cellular uptake efficiency. As expected, the platform is more easily absorbed by endothelial cells and fibroblasts and exhibits outstanding dermal penetration performance and antioxidant properties. Encouraging results are also observed in infected diabetic wound models, showing improved wound re-epithelialization, collagen deposition, angiogenesis, and accelerated wound healing. Collectively, a biohybrid nanorobot platform that possesses the functionalities of both artificial units and biological components serves as an efficient delivery system to promote diabetic wound repair through dual-enhanced cell and tissue penetration and multistep interventions.

Circular RNAs (circRNAs) play a vital role in diabetic peripheral neuropathy. However, their expression and function in Schwann cells in individuals with diabetic peripheral neuropathy remain poorly understood. Here, we performed protein profiling and circRNA sequencing of sural nerves in patients with diabetic peripheral neuropathy and controls. Protein profiling revealed 265 differentially expressed proteins in the diabetic peripheral neuropathy group. Gene Ontology indicated that differentially expressed proteins were mainly enriched in myelination and mitochondrial oxidative phosphorylation. A real-time polymerase chain reaction assay performed to validate the circRNA sequencing results yielded 11 differentially expressed circRNAs. circ_0002538 was markedly downregulated in patients with diabetic peripheral neuropathy. Further in vitro experiments showed that overexpression of circ_0002538 promoted the migration of Schwann cells by upregulating plasmolipin (PLLP) expression. Moreover, overexpression of circ_0002538 in the sciatic nerve in a streptozotocin-induced mouse model of diabetic peripheral neuropathy alleviated demyelination and improved sciatic nerve function. The results of a mechanistic experiment showed that circ_0002538 promotes PLLP expression by sponging miR-138-5p, while a lack of circ_0002538 led to a PLLP deficiency that further suppressed Schwann cell migration. These findings suggest that the circ_0002538/miR-138-5p/PLLP axis can promote the migration of Schwann cells in diabetic peripheral neuropathy patients, improving myelin sheath structure and nerve function. Thus, this axis is a potential target for therapeutic treatment of diabetic peripheral neuropathy.

Small extracellular vesicles (sEVs) from adipose‐derived stem cells (ADSCs) have gained great attention and have been widely used in cell‐free therapies for treating diabetic non‐healing wounds in recent years. However, further clinical application of ADSC‐sEVs have been limited due to their unsolvable defects, including cumbersome extraction procedure, high cost, low yield, etc. Thus, we urgently need to find one therapeutic reagent that could not only accelerate diabetic wound healing as ADSC‐sEVs but also overcome these shortcomings. As the extraction process of adipose tissue‐derived sEVs (AT‐sEVs) is quite simple and labor saving, we put our focus on the efficiencies of white adipose tissue‐derived sEVs (WAT‐sEVs) and brown adipose tissue‐derived sEVs (BAT‐sEVs) in diabetic wound repair. After successfully isolating WAT‐sEVs and BAT‐sEVs by ultracentrifugation, we thoroughly characterized them and compared their diabetic wound healing capabilities both in vitro and in vivo. According to our study, AT‐sEVs possess similar competence in diabetic wound healing as compared with ADSC‐sEVs. While the effect of BAT‐sEVs is not as stable as WAT‐sEVs and ADSC‐sEVs, the repair efficiency is also slightly lower than the other two sEVs in some cases. In summary, we are the first to discover that WAT‐sEVs show great potential in diabetic wound repair. With advantages that are specific to tissue‐derived sEVs (Ti‐sEVs) such as time‐ and cost‐saving, high‐yield, and simple isolation procedure, we believe WAT‐sEVs could serve as a novel reliable cell‐free therapy for clinical diabetic wound treatment.

Diabetic wounds are challenging to heal due to high glucose levels, and oxidative stress, impaired immune response and delayed angiogenesis. Hydrogel dressings capable of adapting and improving multiple microenvironments have broad prospects for application in clinical diabetes wound healing. In this study, we developed a photocrosslinked chitosan hydrogel using the antioxidant molecule "lipoic acid", eliminating the need for additional photoinitiators. The obtained hydrogel exhibited respectable adhesion (adhesion strengths to iron, wood and skin are 0.045 MPa, 0.049 MPa and 0.041 MPa, respectively), photo-induced self-healing, and responsiveness to pH, H2O2 and glucose. Notably, as compared to conventional injectable methacrylated chitosan hydrogel, LAMC hydrogels displayed the abilities to regulate the wound environment, such as reducing oxidative stress, blood sugar levels, and pH, and creating a favorable microenvironment for wound healing. Exosomeloaded LAMC hydrogels enabled targeted exosome release based on glucose concentration, pH, and H2O2 to promote angiogenesis and accelerate healing. Our study offers a novel method for preparing injectable chitosan hydrogels and introduces a new strategy for developing drug-delivery systems that effectively promote diabetic wound healing, potentially transforming current therapeutic approaches.

Diabetic wounds are a serious complication of diabetes mellitus (DM) that can lead to persistent infection, amputation, and even death. Prolonged oxidative stress has been widely recognized as a major instigator in the development of diabetic wounds; therefore, oxidative stress is considered a promising therapeutic target. In the present study, Keap1/Nrf2 signaling was confirmed to be activated in streptozotocin (STZ)-induced diabetic mice and methylglyoxal (MGO)-treated human umbilical vein endothelial cells (HUVECs). Knockdown of Keap1 by siRNA reversed the increase in Keap1 levels, promoted the nuclear translocation of Nrf2, and increased the expression of HO-1, an antioxidant protein. To explore therapeutic delivery strategies, milk-derived exosomes (mEXOs) were developed as a novel, efficient, and non-toxic siRNA carrier. SiRNA-Keap1 (siKeap1) was loaded into mEXOs by sonication, and the obtained mEXOs-siKeap1 were found to promote HUVEC proliferation and migration while relieving oxidative stress in MGO-treated HUVECs. Meanwhile, in a mouse model of diabetic wounds, injection of mEXOs-siKeap1 significantly accelerated diabetic wound healing with enhanced collagen formation and neovascularization. Taken together, these data support the development of Keap1 knockdown as a potential therapeutic strategy for diabetic wounds and demonstrated the feasibility of mEXOs as a scalable, biocompatible, and cost-effective siRNA delivery system. The therapeutic effect of siKeap1-loaded mEXOs on diabetic wound healing was assessed. First, we found that the expression of Keap1 was upregulated in the wounds of diabetic mice and in human umbilical vein endothelial cells (HUVECs) pretreated with methylglyoxal (MGO). Next, we extracted exosomes from raw milk by differential centrifugation and loaded siKeap1 into milk-derived exosomes by sonication. The in vitro application of the synthetic complex (mEXOs-siKeap1) was found to increase the nuclear localization of Nrf2 and the expression of the antioxidant protein HO-1, thus reversing oxidative stress. Furthermore, in vivo mEXOs-siKeap1 administration significantly accelerated the healing rate of diabetic wounds (Scheme 1). Scheme 1 Schematic diagram. A Synthesis of mEXOs-siKeap1 complex. B Mechanism of mEXOs-siKeap1 in vitro. C The treatment effect of mEXOs-siKeap1 on an in vivo mouse model of diabetic wounds.

It is a widespread and difficult problem that refractory diabetic wounds have a poor local environment and prolonged inflamma-tory irritation. Tumor cell-derived exosomes play an important role in the development of tumors, as they can promote tumor cell proliferation, migration, and invasion and enhance tumor cell activity. However, tumor tissue-derived exosomes (Ti-Exos) have been less studied, and it is unclear how they affect wound healing. In this study, we extracted Ti-Exos from human oral squa-mous carcinoma and paracancerous tissue by ultracentrifugation, size exclusion chromatography, and ultrafiltration and per-formed exosome characterization. In vitro, the oral squamous cell carcinoma tissue-derived exosomes (OSCC Ti-Exos) promoted the proliferation and migration of endothelial cells, keratinocytes, and fibroblasts. In addition, in vivo experiments showed that the OSCC Ti-Exos accelerated the healing of diabetic wounds and were safe in mice. In contrast, there was no promoting effect of paracancerous tissue-derived exosomes either in vivo or in vitro. In conclusion, OSCC Ti-Exos promoted the healing of dia-betic wounds, demonstrated preliminary biosafety in mice, and have promise as therapeutic applications.NEW & NOTEWORTHY Diabetic wound healing has become a public health issue that lacks effective treatment. We collected oral squamous cell carcinoma samples and paracancerous tissue and extracted Ti-Exos for verification. In vitro assays revealed that OSCC Ti-EVs could enhance the proliferation and migration of endothelial cells, keratinocytes, and fibroblasts in diabetic cell model. In vivo assays also verified that OSCC Ti-Exos could promote diabetic wound healing, demonstrated preliminary bio-safety in mice, and have promise as therapeutic applications.

Porous metal-organic framework (MOF) liquids with permanent porosity, good fluidity, and fine dispersion attract broad attention in catalysis, transportation, gas storage, and chemical separations. Yet, the design and synthesis of porous MOF liquids for drug delivery remain less explored. Herein, a simple and general strategy is reported to prepare ZIF-91 porous liquid (ZIF-91-PL) via surface modification and ion exchange. The cationic nature of ZIF-91-PL not only renders it antibacterial but also with high curcumin loading capacity and sustained release. More importantly, the acrylate group on the grafted side chain of ZIF-91-PL makes it feasible to crosslink with modified gelatin through light curing, and the obtained hydrogel shows a significantly improved healing effect on the wound of diabetes. This work demonstrates for the first time, a MOF-based porous liquid for drug delivery, and the further fabrication of composite hydrogel may have potential applications in biomedical science.

Promoting the healing of diabetic wounds remains a major challenge in scientific research today. A star-like eight-arm cross-linker octafunctionalized POSS of benzaldehyde-terminated polyethylene glycol (POSS-PEG-CHO) was synthesized, and crosslinked with hydroxypropyltrimethyl ammonium chloride chitosan (HACC) via Schiff base reaction to obtain Chitosan-based POSS-PEG hybrid hydrogels. The designed composite hydrogels exhibited strong mechanical strength, injectability, excellent self-healing efficiency, good cytocompatibility and antibacterial properties. Furthermore, the composite hydrogels could accelerate cells migration and proliferation, as expected by remarkably promoting wound healing in diabetic mice. The wounds treated with the composite hydrogels displayed faster regeneration of epithelial tissue, fewer inflammatory cells, more collagen deposition and higher expression level of VEGF. Therefore, Chitosan-based POSS-PEG hybrid hydrogel has great application potential as a dressing for promoting the healing of diabetic wounds.

Abstract Background Skin cutaneous melanoma (SKCM) remains the deadliest form of skin cancer. However, mechanism of prognosis of SKCM is not yet clear, and accurate prediction of the prognosis remains difficult. Here, we developed and validated three prognostic risk models based on immune cell infiltration, DNA methylation features, and immune-related genes for SKCM patients.Methods We downloaded the datasets from high-dimensional public databases. Univariate and multivariable Cox regression analysis was performed to develop models based on prognostic tumor-infiltrating immune cells, methylation related DEGs (mrDEGs), and immune-related genes (IRGs). Functional enrichment analysis was performed using clusterProfiler and GSVA R package. Prediction of sensitivity to drugs was conducted using pRRophetic R package. The prognostic value of these models was assessed using survival analysis and receiver operating characteristic curve analysis.Results The immune cell model was constructed based on 5 immune cell subtypes. Nine mrDEGs were identified to develop the methylation model. Furthermore, the prognostic IS model based on 5 IRGs was established. These models showed good performance to predict the prognosis of SKCM patients. The IS and methylation score were demonstrated to be associated with immune cell infiltration, microsatellite instability, and tumor mutational burden in SKCM. Moreover, the IS could predict the sensitivity to drugs and the responsiveness to immunotherapy. Finally, IHC staining of the clinical samples confirmed the increased expression of the prognostic IRGs.Conclusions These risk models based on immune cell infiltration, DNA methylation, and IS could be used to predict the survival of SKCM patients and further to guide treatment decisions.

Extracellular vesicles (EVs) are particles released from cells, and their lipid bilayer membrane encloses large amounts of bioactive molecules that endow EVs with intercellular or inter-tissue communicational abilities. Tissue-derived extracellular vesicles (Ti-EVs) are EVs directly separated from the interstitial space of tissue. They could better reflect the actual physiological or pathological state of the tissue microenvironment compared with cell line-derived EVs and biofluid EVs, indicating their potential roles in elucidating the underlying mechanism of pathogenesis and guiding the diagnosis, therapeutic targeting, and cell-free treatment of diseases. However, there have been a relatively limited number of investigations of Ti-EVs. In this review, we have summarized general procedures for Ti-EVs isolation, as well as some caveats with respect to operations after the isolation step, such as purification and storage. In addition, we have also briefly concluded the current research trends on EVs from various normal and tumor tissues, aiming to cast new light on the future research direction of Ti-EVs.

Non-healing wound, with limited treatment options, remains a prevalent complication of diabetes mellitus. The underlying causes wherein include oxidative stress injury, bacterial infection, cellular dysfunction, and persistent inflammation. Acellular Dermal Matrix (ADM), a wound dressing composed of natural extracellular matrix and abundant bioactive factors, has been successfully developed to treat various wounds, including burns and diabetic ulcers. Protocatechualdehyde (PA) & trivalent iron ion (Fe3+) complex (Fe3+@PA) exhibits potential antioxidant and antibacterial properties. In this study, we developed a dual hydrogel network by combining Fe3+@PA complex-modified ADM with light-cured gelatin (GelMA), supplemented with exosomes derived from human umbilical vein endothelial cells (HUVEC-Exos), to create an ADM composite hydrogel system (ADM-Fe3+@PA-Exos/GelMA) with antioxidant, antibacterial, and cell-promoting functions for diabetic wound treatment. Through in vitro experiments, we investigated the biosafety, antioxidant and antibacterial properties of ADM composite hydrogel. Furthermore, we examined the protective effects of ADM composite hydrogel on diabetic wound. The above experiments collectively demonstrate that our ADM-Fe3+@PA-Exos/GelMA hydrogel promotes diabetic wound healing by eliminating bacterial infection, reduced the reactive oxygen species (ROS) levels, protecting cells against oxidative stress damage, promotingcollagen deposition and angiogenesis, which provides a promising strategy to optimize ADM for diabetic wound treatment.