Engineered immunostimulatory H 2 O 2 ‐producing microreactors driven by yeast as localized living cancer therapeutics
Wenqian He, Chunjie Wang, Minming Chen, Weihao Yang, Bin Yu, Yuhang Hu, Hengze Ding, Yifan Yan, Zhijuan Yang, Liangzhu FengAbstract
The development of locoregional cancer therapeutics capable of achieving tumor‐selective cytotoxicity while simultaneously eliciting systemic antitumor immunity remains an urgent clinical need. Herein, we present a hypoxia‐responsive living microreactor (designated as SACP) fabricated through co‐encapsulation of Saccharomyces boulardii (S.b.) , alcohol oxidase (ALOD), and calcium carbonate nanoparticles (nano‐CaCO 3 ) within a photo‐crosslinked polyethylene glycol diacrylate microsphere. SACP leverages sequential S.b .‐mediated anaerobic alcohol production to fuel ALOD‐catalyzed H 2 O 2 generation, where nano‐CaCO 3 protects ALOD from denaturation during the photo‐crosslinking process and yeast‐induced acidification. SACP demonstrates selective cancer cell killing with minimal impact on normal cells, while progressively releasing immunogenic yeast cell walls. Upon intratumoral injection, SACP achieves tumor‐selective S.b . colonization, cascading H 2 O 2 production, and activation of both innate and adaptive antitumor immunity, leading to synergistic tumor growth suppression, which could be further augmented by immune checkpoint blockade therapy. Moreover, SACP is capable of functioning as a living embolic microsphere, significantly inhibiting orthotopic liver tumor growth in rats without safety concerns via transcatheter arterial embolization therapy. This study establishes the controllable preparation of probiotic yeast driven living cancer therapeutics that simultaneously enable selective cancer cell killing and activation of systemic antitumor immunity, offering promise for locoregional cancer treatment.