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In this work, a new strategy of local synergistic hydrogenochemotherapy is proposed to attenuate side effects and enhance therapeutic efficacy based on the anti\u2010cancer selectivity and normal cells\u2010protecting effect of H<jats:sub>2<\/jats:sub>, and construct a novel anti\u2010cancer formulation of rectal suppository (5\u2010FU\/CSN@FAG) by fatty acid glycerides (FAG) encapsulating 5\u2010fluorouracil (5\u2010FU, a first\u2010line drug for colorectal cancer treatment) and cerium silicide nanoparticles (CSN) with a sustained hydrolytic H<jats:sub>2<\/jats:sub> release behavior which is synchronous with 5\u2010FU release. The 3\u2010week treatment with the suppository once a day can not only completely eradicate colon tumors without tumor recurrence after suppository administration withdrawal, but also efficiently protect the intestinal tract from chemotherapeutic damage. Mechanistically, H<jats:sub>2<\/jats:sub> generated by CSN reduces the toxicity of 5\u2010FU to normal cells in the intestinal tract by scavenging over\u2010expressed reactive oxygen species and correcting energy metabolism, and also assists 5\u2010FU to promote the apoptosis of colon tumor cells by inhibiting their respiration through a CO signaling pathway. High biosafety and therapeutic validity endow the developed suppository with a high potential for clinical translation.<\/jats:p>","DOI":"10.1002\/adhm.202404054","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T02:25:22Z","timestamp":1737512722000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A Sustained H<sub>2<\/sub>\/Fluorouracil\u2010Releasing Suppository for High\u2010efficacy and Low\u2010Toxicity Hydrogenochemotherapy of Colon Cancer"],"prefix":"10.1002","volume":"14","author":[{"given":"Danyang","family":"Chen","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of Hydrogen Science &amp; Center of Hydrogen Science School of Materials Science and Engineering Shanghai Jiao Tong University  Shanghai 200240 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Hydrogen Science &amp; 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