A Sustained H2/Fluorouracil‐Releasing Suppository for High‐efficacy and Low‐Toxicity Hydrogenochemotherapy of Colon Cancer

Abstract To attenuate the intestinal toxicity of chemotherapeutic drugs from rectal suppositories and enhance their chemotherapeutic outcome is greatly significant, but maintains a challenge. In this work, a new strategy of local synergistic hydrogenochemotherapy is proposed to attenuate side effects and enhance therapeutic efficacy based on the anti‐cancer selectivity and normal cells‐protecting effect of H 2 , and construct a novel anti‐cancer formulation of rectal suppository (5‐FU/CSN@FAG) by fatty acid glycerides (FAG) encapsulating 5‐fluorouracil (5‐FU, a first‐line drug for colorectal cancer treatment) and cerium silicide nanoparticles (CSN) with a sustained hydrolytic H 2 release behavior which is synchronous with 5‐FU release. The 3‐week 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 2 generated by CSN reduces the toxicity of 5‐FU to normal cells in the intestinal tract by scavenging over‐expressed reactive oxygen species and correcting energy metabolism, and also assists 5‐FU 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.