A pH-responsive nanomedicine inspired by the traditional Chinese mineral medicine pyritum for dual-modal imaging-guided combination therapy for osteosarcoma

Osteosarcoma remains a challenging malignancy due to its aggressive metastasis and resistance to conventional therapies. But the integration of nanotechnology with traditional Chinese medicine offers a transformative approach to overcoming challenges in herbal utilization and cancer therapy. Here, we report the discovery of self-assembled nanoparticles formed during the co-decoction of pyritum and corni fructus, representing a novel mechanism underlying traditional Chinese medicine synergy. Notably, the nanoparticles demonstrate magnetic resonance imaging (MRI) capability with a high T₁ relaxation rate and low r₂/r₁ ratio (1.53), positioning them as promising T₁ contrast agents. Inspired by this natural self-assembly process, we engineer a pH-responsive nanoplatform by conjugating gallic acid, polydopamine, and alendronate onto porous FeS₂ nanoparticles (FGPA). FGPA achieves multi-therapy through drug release, photothermal ablation, H₂S-mediated bioenergetic collapse, and ferroptosis induction. In vivo orthotopic models demonstrate almost tumor regression treated with FGPA and near-infrared irradiation, while maintaining biosafety. Additionally, FGPA serves as a dual-modal photoacoustic (PA)/MRI contrast agent, enabling image-guided therapy with pH-responsive T₁ relaxation enhancement. This work bridges traditional Chinese medicine and nanotechnology, establishing a paradigm for developing multifunctional traditional Chinese medicine-based theranostic agents.