Mitochondrial dysfunction, particularly when associated with the mitochondrial DNA (mtDNA) activated cGAS-STING signaling pathway, represents a key pathogenic mechanism contributing to excessive inflammation. Therapeutic targeting of mitochondrial homeostasis coupled with precise modulation of mtDNA release emerges as a promising yet underexplored strategy to suppress pathological inflammation and promote chronic wound healing. Herein, epigallocatechin gallate-quercetin co-assembled nanoparticles (EQ NPs) were engineered to inhibit mtDNA-mediated inflammatory cascades through mitochondria-targeted multimodal mtDNA level control. Primarily, EQ NPs reduced the formation of oxidized mtDNA fragments (Ox-mtDNA). Then, EQ NPs inhibited the excessive opening of the mitochondrial permeability transition pore, preventing Ox-mtDNA cytoplasmic leakage. Subsequently, the escaped mtDNA fragments were neutralized by EQ NPs through polyphenol-mediated adsorption. Finally, mitophagy was upregulated to selectively eliminate damaged mitochondria. This well-designed strategy significantly inhibited the activation of the mtDNA-mediated cGAS-STING pathway, relieved the release of inflammatory factors, and promoted anti-inflammatory phenotype polarization of macrophages. In vivo, EQ NPs promoted chronic wound healing by bacteriostasis, anti-inflammation, immunomodulation, and accelerated angiogenesis. Overall, the study establishes a sequential mitochondrial quality control paradigm in which the inflammatory cascade is interrupted by multimodal and full-chain mtDNA scavenging, providing a promising candidate for the treatment of inflammatory diseases and chronic wound healing.
