Scaffold-mediated miRNA-155 inhibition promotes regenerative macrophage polarisation leading to anti-inflammatory, angiogenic and neurogenic responses for wound healing

Chronic wounds represent a significant clinical challenge due to persistent inflammation and impaired nerve regeneration that delay healing. Conventional treatments often yield inconsistent and limited success. Combinatorial strategies that integrate biomaterial scaffolds with gene delivery offer a promising approach to promote tissue repair. MicroRNAs (miRNAs), particularly miRNA-155, are key regulators of wound healing. miRNA-155 is highly expressed in inflammatory conditions and modulates macrophage activation, polarisation, and nerve regeneration. In this context, this study introduces a miRNA-155 inhibitor-activated scaffold designed to modulate the chronic wound environment by inhibiting miRNA-155. miRNA-155 inhibitor complexed GET nanoparticles were incorporated into collagen-glycosaminoglycan (CG) scaffolds. Scaffold-mediated miRNA-155 inhibition in both non-polarised (M0) and pro-inflammatory (M1) macrophages promoted anti-inflammatory (M2) polarisation, confirmed by molecular and protein analysis. The regenerative potential of this macrophage polarisation was validated through inflammatory and angiogenic functional assays with endothelial cells. In parallel, scaffold-mediated miRNA-155 inhibition in dorsal root ganglia (DRG) enhanced axonal regrowth, essential for the synergistic repair of chronic wounds across the skin-nerve axis. In vivo implantation in a chick model demonstrated successful scaffold integration without disrupting vascular development. Collectively, these findings establish the miRNA-155 inhibitor-activated scaffold as a multi-faceted regenerative platform with anti-inflammatory, angiogenic, and neurogenic outcomes for chronic wound healing applications. • miRNA-i-activated scaffolds promote pro-regenerative (M2) macrophage polarisation. • Macrophage secretome from miRNA-i-activated scaffolds support angiogenic outcomes. • Dorsal root ganglia on miRNA-i-activated scaffolds show promising neurogenic outcomes. • In vivo implantation of miRNA-i-activated scaffolds displays successful integration.