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, both of which delay healing. Conventional treatments often yield limited success and inconsistent outcomes, especially in complex and recurring wounds. Combinatorial strategies that integrate biomaterial scaffolds with gene delivery offer a promising approach to promote tissue repair. MicroRNAs (miRNAs), particularly miRNA-155, have emerged as crucial regulators of wound healing. MiRNA-155 is highly expressed in inflammatory conditions and plays a key role in 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 characterised and incorporated into collagen-glycosaminoglycan (CG) scaffolds. These supported dermal fibroblast and endothelial cell growth while enabling controlled inhibitor release. Scaffold-mediated miRNA-155 inhibition in both non-polarised (M0) and pro-inflammatory (M1) macrophages promoted anti-inflammatory (M2) polarisation. Macrophage secretome analysis showed reduced inflammatory cytokines and increased angiogenic growth factor secretion in both conditions. The regenerative potential of the miRNA-i-activated scaffold via macrophage polarisation was validated through inflammatory and angiogenic functional assays with endothelial cells. In parallel, scaffold-mediated miRNA-155 delivery to dorsal root ganglia (DRG) promoted neurogenic outcomes through enhanced axonal regrowth, essential for the synergistic repair of chronic wounds across the skin-nerve axis. In vivo implantation of miRNA-155 inhibitor-activated scaffolds in chicks demonstrated successful integration without disrupting vascular network formation. Collectively, these findings establish the miRNA-155 inhibitor-activated scaffold as a regenerative platform with anti-inflammatory, pro-angiogenic, and neurogenic outcomes, offering a multifaceted solution for chronic wound healing applications.