Injectable Cu2+ loaded rhein hydrogel for cross-amplifying osteosarcoma apoptosis and cuproptosis epitranscriptomically.

Osteosarcoma (OS) remains a formidable clinical challenge due to its aggressive nature, early metastasis, and resistance to conventional therapies. Here, we report an injectable Cu2+-loaded rhein hydrogel (RCugel) that integrates sonodynamic therapy (SDT) and cuproptosis with RNA epitranscriptomical regulation for OS treatment. After administration, RCugel released Cu2+ and rhein to trigger cuproptosis and generated singlet oxygen to induce apoptosis under sonication, respectively. Concurrently, Cu2+ produced additional ROS to amplify apoptosis by reacting with intracellular GSH via a Fenton-like reaction while rhein downregulated ATP7B levels via inhibiting "FTO/DACT1/β-catenin/ATP7B″ axis to further amplify cuproptosis efficiency. Collectively, our study demonstrates that RCugel's synergistic induction of crossing amplification between apoptosis and cuproptosis via epitranscriptomic remodeling represents a potent, translational strategy for improving osteosarcoma therapy.