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

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.