Direct Visualization of Self-Mineralized Biohybrid-Triggered Apoptosis-Ferroptosis Synergistic Tumor Therapy by Cryo-Soft X-ray Tomography.

Bionano robots have been recognized as a tumor-selective and effective platform for therapeutic outcomes as they synergize the merits of living organisms and nanoparticles. Here, we construct a self-mineralized system (denoted as SO@FeS) by employing the facultative anaerobic bacterium Shewanella oneidensis MR-1 to biosynthesize FeS NPs for effective cancer therapy with dual cell death pathways. Biogenic FeS NPs are embedded into the cell surface with inherent photothermal conversion ability and low crystallinity and tend to simultaneously release Fe2+ and hydrogen sulfide (H2S) in an acidic environment. As a result, the obtained SO@FeS hybrid can couple the versatility of the nanoparticles with the respiration and tumor-targeting capacities of bacterium, ultimately leading to the collaborative clearance of tumor cells. Specifically, cryo-soft X-ray tomography (cryo-SXT) is a near-native 3D imaging modality that directly displays the trafficking pathway of SO@FeS in cancer cells. More importantly, cryo-SXT captures the 3D maps of SO@FeS-initiated ferroptosis and apoptosis, as evidenced by the remodeling of cytoplasmic organelles. This work offers valuable theoretical insights from the perspective of organelle morphology, links subcellular reorganization and cell death pathways, and facilitates the design of living nanoplatforms that integrate multiple therapies.