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

Abstract

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.