Triple-targeting miRNA-loaded core-shell nanoparticles in injectable hydrogel enable coordinated diabetic wound repair

Diabetic wound healing is critically impaired by dysregulated macrophage polarization, compromised endothelial angiogenic function, and diminished fibroblast proliferation/migration under persistent hyperglycemia. Current therapies, predominantly focused on single-cell targeting, lack coordinated modulation across these key cellular components. We developed a novel triple-targeting core-shell nanoparticle (miR-RPC) leveraging the shared integrin αvβ3 receptor on macrophages, endothelial cells, and fibroblasts to address this limitation. miR-RPC features an RGD/phosphatidylserine (PS)-modified lipid shell encapsulating a chitosan/​​miR-146a-5p​​ core. This miRNA was selected as a model RNA because of its widely recognized beneficial role in three key cell types in wound healing. The RGD peptide enables specific αvβ3-mediated triple-targeting. The anionic lipid PS facilitates core-shell assembly via electrostatic interaction with the cationic chitosan/RNA core and mimics apoptotic signals to enhance macrophage phagocytosis and phenotypic transition. miR-RPC effectively reprogrammed macrophages towards the M2 phenotype, restored endothelial angiogenic capacity under high glucose, and stimulated fibroblast proliferation, migration, and collagen secretion. Incorporated into a gelatin methacrylate (GelMA)/oxidized hyaluronic acid (OHA) double cross-linked hydrogel (GelO), miR-RPC@GelO significantly accelerated diabetic wound healing in rat models, demonstrating reduced inflammation, increased vascular density, and enhanced collagen deposition. This innovative triple-targeting system achieves coordinated diabetic wound repair through synergistic "immunomodulation-angiogenesis-collagen deposition" mechanisms, offering a promising therapeutic approach. Furthermore, the successful preparation of miR-RPC expands the application of anionic lipids in RNA delivery systems and highlights its potential as a versatile gene delivery vector.