Mitochondria-Targeted Multimodal Nanotherapeutics Suppress Oxidized mtDNA-Driven Inflammation at the Source.

Oxidized mitochondrial DNA (Ox-mtDNA) fragments escaping from mitochondria trigger a potent inflammatory cascade that endangers cellular and tissue integrity. Strategies against pre-existing mtDNA-driven inflammation have been developed. However, the inhibition of emerging Ox-mtDNA fragments remains a critical challenge due to continual leakage from stressed mitochondria. Here, we present a source-control nanodelivery strategy that targets Ox-mtDNA to prevent the generation of fragments and eliminate existing ones. To this end, a small molecule inhibitor FI is specifically designed to selectively target mitochondrial flap endonuclease 1 (mitochondrial FEN1), thereby inhibiting Ox-mtDNA cleavage and the subsequent leakage of fragments. To facilitate the precise and efficient delivery of FI to inflammation-associated cells, we engineered a hyaluronic acid (HA) functionalized nanocarrier, designated Se-FI@Lip-HA, which encapsulates selenium nanoparticles bearing FI (Se-FI NPs) within phospholipid vesicles. The SeNPs further scavenge reactive oxygen species (ROS) and promote autophagy-mediated clearance of leaked mtDNA. Acute respiratory distress syndrome (ARDS), as a severe inflammatory lung disorder, is used as a proof-of-concept model. Se-FI@Lip-HA multimodally suppresses inflammatory signaling activated by Ox-mtDNA at the source and effectively alleviates lung tissue injury. This strategy offers a broadly applicable therapeutic avenue for Ox-mtDNA-driven pathologies in ARDS and other inflammatory diseases.