Cascade-targeting pH/ROS microneedles promote scarless diabetic wound healing by macrophage metaboimmune reprogramming.

Abstract

Precise macrophage modulation is essential for diabetic wound treatment, yet mitochondrial dysfunction often sustains proinflammatory states. We developed cascade-targeting nanoparticles [epigallocatechin-3-gallate and metformin nanoparticles modified with mannose (EM/Man NPs)] to regulate macrophage mitochondria, integrated into a detachable core-shell microneedle patch (EM/Man MNs) made of quaternary ammonium chitosan and reactive oxygen species (ROS)-degradable polymer. The patch offered high penetration and antibacterial activity, while its ROS-sensitive core released EM/Man NPs to scavenge ROS, restore adenosine 5'-triphosphate production, and reestablish redox balance. The NPs further activated the adenosine 5'-monophosphate-activated protein kinase/Sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator 1α axis to promote mitochondrial biogenesis and oxidative phosphorylation, repolarizing macrophages to an anti-inflammatory phenotype. In diabetic mice, EM/Man MNs accelerated healing via bacterial clearance, immune reprogramming, angiogenesis, and collagen deposition while inhibiting scar formation through interleukin-17 and phosphatidylinositol 3-kinase-Akt suppression. This cascade-targeting strategy for modulating macrophage mitochondria to regulate immunity and redox homeostasis provides a previously unidentified approach for designing tissue engineering materials.