A dual-action core-shell microneedle system restores mitochondrial function and accelerates healing in diabetic wounds.

Diabetic wounds remain a significant clinical challenge due to persistent oxidative stress, chronic inflammation, and vascular dysfunction. Leveraging single-cell RNA sequencing, we identified voltage-dependent anion channel 1 (VDAC1) as a key endothelium target upregulated twofold in diabetic wounds. Mechanistically, this upregulation triggers VDAC1 oligomerization and the leakage of mitochondrial damage-associated molecular patterns, which subsequently activates the NLRP3 inflammasome and sustains inflammation. Here, we report a dual-action core-shell microneedle system for sequential therapy. The ROS-responsive shell incorporates cerium oxide nanoenzymes, providing rapid scavenging and potent antimicrobial activity (> 95% bacterial clearance). The photo-crosslinkable GelMA core encapsulates VBIT-4-loaded lipid nanoparticles, which provides sustained inhibition of VDAC1 oligomerization, thereby blocking DAMPs release and NLRP3 activation. This strategy restored mitochondrial function and shifted macrophages toward a pro-regenerative phenotype (M2/M1 ratio from 0.19 to 1.58). In diabetic mice, treatment significantly accelerated healing, breaking the typical therapeutic plateau to achieve > 95% wound closure by day 14, accompanied by enhanced vascularization and reduced inflammation. Transcriptomic analysis confirmed suppression of inflammatory signaling and activation of pro-angiogenic pathways. Importantly, therapeutic efficacy was replicated in a diabetic pig model, underscoring high translational potential. This sequential delivery platform offers a promising strategy for diabetic wound management.