An immuno-chemotherapeutic bone scaffold for tumor eradication and bone regeneration in drug-resistant osteosarcoma.

Abstract

Postoperative management of osteosarcoma remains hindered by several critical challenges, including platinum-based chemoresistance, insufficient antitumor immune responses, and the difficulty of synchronously repairing large bone defects. Addressing these issues requires strategies capable of coordinating tumor eradication, immune modulation, and bone regeneration within the dynamic postoperative microenvironment. In this study, we developed a near-infrared (NIR)-responsive intelligent composite bone scaffold that integrates a reducible platinum (IV) prodrug (Pt (IV)) and cucurbitacin B (CuB) via hollow mesoporous silica and polydopamine interfacial engineering, enabling dual responsiveness to tumor-associated cues and exogenous photonic stimulation. Mechanistically, controlled CuB release suppresses DNA damage repair, amplifies Pt (IV)-induced DNA damage, and reverses platinum resistance, while the combined action of Pt (IV) and CuB induces immunogenic cell death and activates the cGAS-STING pathway, thereby remodeling an antitumor immune microenvironment. Concurrently, sustained Si⁴⁺ release and CuB synergistically promote angiogenesis and osteogenic differentiation, establishing a regenerative niche for bone reconstruction. <i>In vivo</i> studies further demonstrate that the scaffold exhibits microenvironment-responsive and externally triggered regulatory capability. During the tumor suppression phase, the acidic tumor microenvironment and NIR stimulation enhance the release of Pt (IV) and CuB, leading to effective inhibition of drug-resistant osteosarcoma. As the local microenvironment progressively normalizes, the system supports osteogenesis and vascularization, ultimately achieving substantial new bone formation and bone bridging without observable systemic toxicity. Taken together, this work presents a multifunctional composite scaffold strategy characterized by microenvironment responsiveness, functional integration, and multi-pathway coordination. This approach provides an integrated solution for postoperative treatment and bone repair in drug-resistant osteosarcoma.