A multifunctional hydrogel loaded with two nanoagents improves the pathological microenvironment associated with radiation combined with skin wounds

Persistent oxidative stress and recurring waves of inflammation with excessive reactive oxygen species (ROS) and free radical accumulation could be generated by radiation. Exposure to radiation in combina-tion with physical injuries such as wound trauma would produce a more harmful set of medical com-plications, which was known as radiation combined with skin wounds (RCSWs). However, little atten-tion has been given to RCSW research despite the unsatisfactory therapeutic outcomes. In this study, a dual-nanoagent-loaded multifunctional hydrogel was fabricated to ameliorate the pathological microen-vironment associated with RCSWs. The injectable, adhesive, and self-healing hydrogel was prepared by crosslinking carbohydrazide-modified gelatin (Gel-CDH) and oxidized hyaluronic acid (OHA) through the Schiff-base reaction under mild condition. Polydopamine nanoparticles (PDA-NPs) and mesenchymal stem cell-secreted small extracellular vesicles (MSC-sEV) were loaded to relieve radiation-produced tissue in-flammation and oxidation impairment and enhance cell vitality and angiogenesis individually or jointly. The proposed PDA-NPs@MSC-sEV hydrogel enhanced cell vitality, as shown by cell proliferation, migra-tion, colony formation, and cell cycle and apoptosis assays in vitro , and promoted reepithelization by at-tenuating microenvironment pathology in vivo . Notably, a gene set enrichment analysis of proteomic data revealed significant enrichment with adipogenic and hypoxic pathways, which play prominent roles in wound repair. Specifically, target genes were predicted based on differential transcription factor expres-sion. The results suggested that MSC-sEV-and PDA-NP-loaded multifunctional hydrogels may be promis-ing nanotherapies for RCSWs.Statement of significanceThe small extracellular vesicle (sEV) has distinct advantages compared with MSCs, and polydopamine nanoparticles (PDA-NPs), known as the biological materials with good cell affinity and histocompatibility which have been reported to scavenge ROS free radicals. In this study, an adhesive, injectable, self-healing, antibacterial, ROS scavenging and amelioration of the radiation related microenvironment hydrogel en-capsulating nanoscale particles of MSC-sEV and PDA-NPs (PDA-NPs@MSC-sEV hydrogel) was synthesized