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Strategies against pre\u2010existing mtDNA\u2010driven inflammation have been developed. However, the inhibition of emerging Ox\u2010mtDNA fragments remains a critical challenge due to continual leakage from stressed mitochondria. Here, we present a source\u2010control nanodelivery strategy that targets Ox\u2010mtDNA 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\u2010mtDNA cleavage and the subsequent leakage of fragments. To facilitate the precise and efficient delivery of FI to inflammation\u2010associated cells, we engineered a hyaluronic acid (HA) functionalized nanocarrier, designated Se\u2010FI@Lip\u2010HA, which encapsulates selenium nanoparticles bearing FI (Se\u2010FI NPs) within phospholipid vesicles. The SeNPs further scavenge reactive oxygen species (ROS) and promote autophagy\u2010mediated clearance of leaked mtDNA. Acute respiratory distress syndrome (ARDS), as a severe inflammatory lung disorder, is used as a proof\u2010of\u2010concept model. Se\u2010FI@Lip\u2010HA multimodally suppresses inflammatory signaling activated by Ox\u2010mtDNA at the source and effectively alleviates lung tissue injury. This strategy offers a broadly applicable therapeutic avenue for Ox\u2010mtDNA\u2010driven pathologies in ARDS and other inflammatory diseases.<\/jats:p>","DOI":"10.1002\/advs.77577","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T04:37:47Z","timestamp":1788323867000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondria\u2010Targeted Multimodal Nanotherapeutics Suppress Oxidized mtDNA\u2010Driven Inflammation at the Source"],"prefix":"10.1002","author":[{"given":"Wen\u2010Ling","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Cao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical 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