Neutrophil-guided pro-efferocytic mRNA platform for accelerated diabetic wound repair

BACKGROUND: The divergent fates of neutrophils play a critical yet complex role in tissue repair. However, how to harness the heterogeneity of neutrophil phenotypes in specific clinical contexts to guide the design of therapeutic materials remains poorly explored. In this study, inspired by the accumulation of apoptotic neutrophils (aNs) and exaggerated formation of neutrophil extracellular traps (NETs) in diabetic wounds, we innovatively developed nano-platform based on Interleukin 4 (IL-4) mRNA-enriched exosomes locally delivered by bisphosphonate (BP)-magnesium (Mg²⁺) coordination hydrogels. RESULTS: Beyond classical anti-inflammatory and glycolysis-modulating effects, we found that diabetic wound-specific accumulation of aNs surprisingly augmented the ability of our hydrogel to upregulate pro-repair genes. Moreover, the hydrogel formulations effectively rescued defective efferocytosis caused by excessive NETs, potentially through upregulating growth arrest specific 6 (Gas6) and myeloid-epithelial-reproductive tyrosine kinase (MerTK) expression. In vivo implantation of the composite hydrogels significantly accelerated the healing rate and improved the quality of skin wounds in diabetic mice. CONCLUSION: In summary, motivated by the divergent fates of neutrophils in diabetic wounds, we successfully engineered a pro-efferocytic platform based on IL-4 mRNA-primed exosomes incorporated into a coordination hydrogel, tailored specifically to promote diabetic wound repair.