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The current anti-inflammatory treatments can be improved by designing a drug delivery system responsive to the inflammatory site biomarker, hydrogen polysulfide (H<jats:sub>2<\/jats:sub>S<jats:sub>n<\/jats:sub>). Here, we report a novel theranostic agent <jats:bold>1<\/jats:bold> (<jats:bold>TA1<\/jats:bold>), consisting of three parts: H<jats:sub>2<\/jats:sub>S<jats:sub>n<\/jats:sub>-mediated triggering part, a two-photon fluorophore bearing mitochondria targeting unit (Rhodol-TPP), and anti-inflammatory COX inhibitor (indomethacin). In vitro experiments showed that <jats:bold>TA1<\/jats:bold> selectively reacts with H<jats:sub>2<\/jats:sub>S<jats:sub>n<\/jats:sub> to concomitantly release both Rhodol-TPP and indomethacin. Confocal-microscopy imaging of inflammation-induced live cells suggested that <jats:bold>TA1<\/jats:bold> is localized in the mitochondria where the H<jats:sub>2<\/jats:sub>S<jats:sub>n<\/jats:sub> is overexpressed. The <jats:bold>TA1<\/jats:bold> reacted with H<jats:sub>2<\/jats:sub>S<jats:sub>n<\/jats:sub> in the endogenous and exogenous H<jats:sub>2<\/jats:sub>S<jats:sub>n<\/jats:sub> environments and in lipopolysaccharide treated inflammatory cells. Moreover, <jats:bold>TA1<\/jats:bold> suppressed COX-2 level in the inflammatory-induced cells and prostaglandin E<jats:sub>2<\/jats:sub> (PGE<jats:sub>2<\/jats:sub>) level in blood serum from inflammation-induced mouse models. In vivo experiments with inflammation-induced mouse models suggested that <jats:bold>TA1<\/jats:bold> exhibits inflammation-site-elective drug release followed by significant therapeutic effects, showing its function as a theranostic agent, capable of both anti-inflammatory therapy and precise diagnosis. Theranostic behavior of <jats:bold>TA1<\/jats:bold> is highly applicable in vivo model therapeutics for the inflammatory disease. <\/jats:p>","DOI":"10.1007\/s40820-021-00689-1","type":"journal-article","created":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T16:03:45Z","timestamp":1628179425000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Mitochondrial H2Sn-Mediated Anti-Inflammatory Theranostics"],"prefix":"10.1007","volume":"13","author":[{"given":"Won Young","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miae","family":"Won","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyoung","family":"Koo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingcai","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong Seung","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,5]]},"reference":[{"key":"689_CR1","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1016\/j.cell.2010.03.006","volume":"140","author":"R Medzhitov","year":"2010","unstructured":"R. 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