Bioengineering Living Biohybrid Therapeutics for Synergistic H 2 S Gaseous‐Photothermal Cancer Eradication

Abstract Hydrogen sulfide (H 2 S)‐mediated gaseous therapies feature high therapeutic efficacy and biosafety in cancer treatment, but conventional H 2 S delivery protocols suffer from poor tumor specificity and uncontrollable release. Here, a living therapeutic biohybrid is developed that integrates engineered microbes for in situ H 2 S production with self‐mineralized copper sulfide (CuS) nanoparticles, enabling synergistic H 2 S gaseous‐photothermal cancer treatment. These engineered facultative anaerobic bacteria Vibrio natriegens continuously produce H 2 S and synthesize CuS nanoparticles, forming Bac@CuS living biohybrids that inhibit the mitochondrial electron transport chain through H 2 S production, leading to increased reactive oxygen species production and subsequent apoptosis of cancer cells. Concurrently, Bac@CuS‐mediated photothermal effect induces hyperthermia, further impairing mitochondrial function and enhancing cancer‐cell death. In vivo studies demonstrate that Bac@CuS living biohybrids feature excellent biocompatibility and have achieved a 95.4% tumor inhibition rate in the breast tumor‐bearing mouse model. The biohybrid therapeutic platform enables the engineered bacteria to produce non‐native effectors alongside with nanoparticles, integrating synthetic biology with nanotechnology and offering a novel approach for efficient cancer eradication.