A miRNA cocktail orchestrates coordinated cellular responses to promote diabetic wound healing.

Background: Chronic wounds, particularly diabetic ulcers, impose significant health and economic burdens globally because of their complex pathology and the limited availability of therapeutic approaches. Multiple microRNAs (miRNAs) play crucial roles in regulating biological processes in wound healing. However, single-miRNA therapies may not fully overcome the multifaceted barriers of impaired wound repair. Efforts to discover more effective wound therapies continue unabated. This study aims to evaluate the therapeutic potential of a multi-miRNA strategy for enhancing diabetic wound repair. Methods: In this study, we developed a microRNA cocktail that targets multiple critical phases of wound healing: inflammation, re-epithelialization, granulation tissue formation, and angiogenesis. This therapeutic cocktail includes locked nucleic acid-modified mimics of miR-19b-3p, miR-132-3p, and miR-31-5p, along with an inhibitor of miR-92a-3p, which are delivered via in vivo-jetPEI as the carrier, addressing the multifaceted nature of wound repair mechanisms. The wound healing efficacy of the cocktail was systematically evaluated in mouse models of acute and chronic wounds. Results: Local application of the miRNA cocktail to wounds markedly enhanced acute wound healing in wild-type mice, outperforming the effects of the individual miRNAs. Moreover, the miRNA cocktail accelerated diabetic wound healing by orchestrating coordinated cellular responses at the wound site and significantly decreasing inflammatory cytokine expression and CD68+ macrophage migration while promoting re-epithelialization, angiogenesis, and granulation tissue formation. Notably, the cocktail also facilitated nerve regeneration in the wound area at day 30 postinjury. Conclusions: Our findings suggest that this miRNA cocktail has a potential therapeutic value for revitalizing the healing process in chronic wounds. Therefore, further investigations in controlled clinical trials are warranted to confirm the efficacy and applicability of this miRNA cocktail in a clinical setting.