DNA hydrogel-delivered hypoxic exosomes alleviate radiation-induced skin injury by stabilizing AKT

Radiation-induced skin injury (RISI) is a common and refractory complication during tumor radiotherapy, characterized by radiation stress-induced impairment of keratinocyte viability and regenerative signaling, ultimately leading to delayed skin repair. Recently, hypoxia-preconditioned adipose-derived stem cell-derived exosomes (A-Hexos), a cell-free therapeutic strategy with favorable biocompatibility, has considerable potential in skin injury repair. However, the underlying mechanisms of A-Hexos in the treatment of RISI have not been fully elucidated, and their delivery efficiency and retention capacity at skin injury sites remain suboptimal. In this study, we aimed to enhance the targeted delivery efficiency of exosomes in skin tissues, systematically evaluate the therapeutic effects of A-Hexos in RISI repair, and elucidate the underlying molecular mechanisms.

In vitro experiments demonstrated that A-Hexos significantly restored the viability, proliferative capacity, and migratory behavior of irradiated keratinocytes (HaCaT). To enhance the local delivery efficiency and tissue retention of exosomes at injured sites in vivo, we constructed a DNA hydrogel-based delivery system loaded with A-Hexos (Gel@A-Hexos), which was engineered through the specific interaction between an exosome membrane protein-specific aptamer (Apt CD63) designed on long DNA strands and the exosomal membrane protein, CD63. In a murine RISI model, Gel@A-Hexos markedly alleviated radiation-induced injury and promoted skin tissue structural reconstruction. Mechanistically, miRNA sequencing revealed that miR-486-5p was significantly enriched in A-Hexos, while proteomic analysis further indicated that Gel@A-Hexos treatment markedly downregulated RNF213 expression and concomitantly upregulated AKT expression in injured skin tissues. Functionally, miR-486-5p delivered by A-Hexos stabilized AKT protein levels by inhibiting RNF213-mediated ubiquitin-dependent AKT degradation, thereby alleviating RISI and promoting tissue repair.

Collectively, this study proposes a long DNA strand-based exosome local delivery hydrogel and elucidates the molecular mechanism by which A-Hexos exert reparative effects on RISI via the miR-486-5p/RNF213/AKT signaling axis, providing new theoretical insights and a potential translational strategy for the precise treatment of RISI.