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Abstract

Chronic diabetic wounds complicated by biofilm infections resist healing because persistent bacterial colonization coexists with microenvironmental imbalances, including oxidative stress and inflammation. Conventional pharmacotherapy and wound care are limited by impaired local perfusion, which hinders both effective biofilm eradication and reversal of the pathological wound microenvironment. We developed an ultrasound-activated core–shell microneedle platform (CCA&Lut@MN) that combines sonodynamic gas cascade antimicrobial therapy with a ROS-responsive microenvironment modulation strategy. Upon ultrasonic stimulation, L-arginine–modified copper–cysteine nanoparticles (CCA) in the microneedle shell generate reactive oxygen species (ROS) and catalyze NO release from L-Arg, producing synergistic oxidative and nitrative stress that yields rapid bactericidal activity and effective biofilm eradication. The microneedle core consists of an ROS-responsive PVA-HP-luteolin hydrogel that degrades in response to elevated ROS in the microenvironment, releasing luteolin. Luteolin scavenges excess ROS and promotes macrophage polarization to the M2 phenotype, thereby enhancing angiogenesis and cell migration. In a diabetic rat wound model infected with MRSA, CCA&Lut@MN markedly reduced wound bacterial load, alleviated local inflammation and improved blood supply, and thereby accelerated wound healing. This microneedle platform produces synergistic antibacterial effects via sonodynamic therapy (SDT)–gas cascade reactions, modulates the pathological microenvironment, and improves local blood supply, offering a promising strategy for treating complex and refractory wounds.