3D-Printed Hydrogel Scaffolds with Sandwich Architecture for Multimodal Therapy of Postoperative Osteosarcoma

Surgical resection combined with adjuvant chemotherapy represents the primary therapeutic strategy for osteosarcoma, yet significant challenges remain in preventing postoperative tumor recurrence and drug resistance. Herein, an engineered sandwich-structured hydrogel scaffold (sandwich/MTO-CuHCF) loading copper hexacyanoferrate nanoparticles (CuHCF) and mitoxantrone (MTO) with multimodal therapy was developed by using in situ stacked 3D-printing technology. The sandwich architecture provided distinct compartmentalization of therapeutic agents, thereby mitigating the risk of physicochemical incompatibility. Upon implantation of the sandwich/MTO-CuHCF scaffold at the tumor resection site, CuHCF and MTO were sequentially and sustainably released. On one hand, CuHCF depleted intracellular glutathione and catalyzed a Fenton-like reaction to generate cytotoxic hydroxyl radicals, leading to effective cancer cell killing. On the other hand, the subsequently released MTO, an anthracycline chemotherapeutic agent, induced DNA damage in tumor cells. Notably, the excellent photothermal conversion efficiency of sandwich/MTO-CuHCF under near-infrared irradiation not only enhanced the Fenton-like reaction through localized hyperthermia but also facilitated photothermal ablation of osteosarcoma cells. Remarkably, in a mouse osteosarcoma resection model, scaffold implantation significantly inhibited tumor recurrence. Our study provides a conceptual framework for the development of implantable scaffolds to achieve effective suppression of postoperative tumor recurrence.