Polyphenol-Metal Mediated Mitochondrial-Targeted Injectable Hydrogel Promotes Diabetic Wound Healing

Diabetic wounds present significant therapeutic challenges, characterized by persistent inflammation, impaired vascular regeneration, and mitochondrial dysfunction, which collectively contribute to delayed healing and a high recurrence rate. To address these limitations, we developed an injectable hydrogel dressing composed of gelatin methacrylate (GelMA), alginate methacrylate (AlgMA), and tannic acid-cobalt ion (TACo) nanoparticles, cross-linked through photopolymerization. The resulting hydrogel exhibited favorable physical properties and pH-responsive release behavior, enabling the sustained release of bioactive components in the acidic wound microenvironment. The hydrogel exhibited outstanding multifunctionality, characterized by a potent free radical scavenging capacity that effectively mitigated oxidative stress. Moreover, it displayed broad-spectrum antibacterial activity against common pathogens including E. coli and S. aureus, and promoted macrophage reprogramming into the pro-regenerative M2 phenotype, thereby addressing chronic inflammation. TACo exhibited efficient mitochondrial targeting capability, preserved mitochondrial membrane integrity, and significantly reduced mitochondrial oxidative stress. In a diabetic rat wound model, hydrogel treatment markedly promoted tissue regeneration by accelerating re-epithelialization, improving collagen architecture, and enhancing the expression of key angiogenic markers, including CD31 and VEGF. Overall, these findings highlight the hydrogel's capacity to concurrently mitigate oxidative stress, resolve inflammatory dysregulation, and restore mitochondrial function, supporting its potential as a promising advanced therapy for refractory diabetic wounds.