Bioengineering Living Biohybrid Therapeutics for Synergistic H2S Gaseous-Photothermal Cancer Eradication.

Hydrogen sulfide (H2S)-mediated gaseous therapies feature high therapeutic efficacy and biosafety in cancer treatment, but conventional H2S delivery protocols suffer from poor tumor specificity and uncontrollable release. Here, a living therapeutic biohybrid is developed that integrates engineered microbes for in situ H2S production with self-mineralized copper sulfide (CuS) nanoparticles, enabling synergistic H2S gaseous-photothermal cancer treatment. These engineered facultative anaerobic bacteria Vibrio natriegens continuously produce H2S and synthesize CuS nanoparticles, forming Bac@CuS living biohybrids that inhibit the mitochondrial electron transport chain through H2S 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.