A universal consuming endogenous H2S strategy using bismuth-metal-organic nanocapsule networks for overcoming osteosarcoma cisplatin resistance.

Osteosarcoma (OS), the most common primary bone malignancy in adolescents, faces limited treatment options and high chemoresistance rates. Hydrogen sulfide (H2S), an endogenously produced gaseous signaling molecule that regulates cellular redox homeostasis, promotes chemoresistance in multiple cancers, but its role in osteosarcoma remains unclear. Here, we identify endogenous H2S as a key driver of cisplatin resistance in osteosarcoma and develop a novel H2S-targeting theranostic platform named bismuth-based metal-organic nanocapsule network (Bi-MONC). The nanocapsule exhibits excellent drug-loading capacity. During circulation, Bi-MONC undergoes gradual size reduction and disassembly into smaller particles while remaining as discrete nanoparticles until it reaches the osteosarcoma site. Furthermore, Bi-MONC binds intracellular H2S to form Bi2S3, enabling in situ photoacoustic imaging of tumors while triggering ferroptosis via endoplasmic reticulum stress and ubiquitin-mediated proteasomal degradation of GPX4, enhancing cisplatin efficacy. This dual-action material overcomes enzymatic redundancy in H2S production, offering a universal approach to scavenge intracellular H2S. Collectively, our study presents an innovative strategy that simultaneously addresses the challenges of precise diagnosis and chemoresistance in osteosarcoma.