Intelligent microneedle patch with cobalt-iron Prussian blue nanozymes for accelerating diabetic wound healing <i>via</i> heme biosynthesis-driven immunomodulation.

Abstract

A complex wound microenvironment with the presence of bacterial infection, overproduction of hydrogen peroxide (H₂O₂), chronic inflammation, poor vascularization and hypoxia wound result in delayed healing of diabetic wounds. In this study, a novel antibacterial microneedle patch integrating cobalt-iron Prussian blue (CFP) nanoenzymes loaded with prodrug 5-aminolevulinic acid (5-ALA) for intelligent, multi-stage therapeutic intervention on diabetic infected wound healing. Specifically, ALA@CFP demonstrated peroxidase (POD)-like activity to initiate the <i>in situ</i> production of hydroxyl radicals in response to elevated H₂O₂ in the wound, which proficiently induced bacterial ferroptosis and dismantled the bacterial biofilms, while the catalase (CAT)-like activity alleviated hypoxia wound conditions <i>via</i> decomposing H₂O₂ to produce oxygen. Simultaneously, Fe²⁺ released from ALA@CFP facilitated the transformation of 5-ALA to heme, significantly amplifying downstream heme oxygenase-1 (HO-1) activity and producing endogenous anti-inflammatory mediators, carbon monoxide and bilirubin. These molecules subsequently restructured the inflammatory wound microenvironment by instigating the polarization of macrophages from the M1-phenotype to the pro-repair M2-phenotype and upregulated the expression of anti-inflammatory factors, thereby fostering cell migration and angiogenesis. When embedded in a methacrylated gelatin/carboxymethyl chitosan hydrogel microneedle matrix, the system enables on-demand deep tissue delivery, achieving simultaneous antibacterial, anti-inflammatory, pro-angiogenic and regenerative effects in an infected diabetic mouse model. This study demonstrates a material-driven, metabolism-amplified strategy for intelligent wound repair, providing a promising platform for next-generation functional biomaterials.