A universal consuming endogenous H2S strategy using bismuth-metal-organic nanocapsule networks for overcoming osteosarcoma cisplatin resistance.
The paper reports that endogenous H2S promotes cisplatin resistance in osteosarcoma and describes a bismuth-based metal-organic nanocapsule platform that scavenges H2S, enables photoacoustic imaging, induces GPX4-linked ferroptosis, and enhances cisplatin efficacy.
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The paper reports that endogenous H2S promotes cisplatin resistance in osteosarcoma and describes a bismuth-based metal-organic nanocapsule platform that scavenges H2S, enables photoacoustic imaging, induces GPX4-linked ferroptosis, and enhances cisplatin efficacy.
Research significance
The supplied abstract supports H2S depletion by Bi-MONC as a reported means of sensitizing osteosarcoma to cisplatin; it remains an inference—not established clinical evidence—that this theranostic strategy could safely reverse cisplatin resistance in patients.
Source 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.