Multiple‐Effect Combined Hydrogels: “Temporal Regulation” Treatment of Osteosarcoma‐Associated Bone Defects with Switchable Hyperthermia and Bioactive Agents

Abstract Achieving the clinically staged treatment of osteosarcoma‐associated bone defects encounters the multiple challenges of promptly removing postoperative residual tumor cells and bacterial infection, followed by bone reconstruction. Herein, a core/shell hydrogel with multiple‐effect combination is designed to first exert antitumor and antibacterial activities and then promote osteogenesis. Specifically, doxorubicin (DOX) is loaded by magnesium‐iron‐based layered double hydroxide (LDH) to prepare LDOX, which is introduced into a thermo‐sensitive hydrogel to serve as an outer shell of the core/shell hydrogel, meanwhile, LDH‐contained liquid crystal hydrogel, abbreviated as LCgel‐L, is served as an inner core. At the early stage of treatment, the dissociation of the outer shell triggered by moderate hyperthermia led to the thermo‐sensitive release of LDOX, which can be targeted for the release of DOX within tumor cells, thereby promptly removing postoperative residual tumor cells based on the synergistic effect of photothermal therapy (PTT) and DOX, and postoperative bacterial infection can also be effectively prevented by PTT simultaneously. More importantly, the dissociation of the outer shell prompted the full exposure of the inner core, which will exert osteogenic activity based on the synergy of liquid crystal hydrogel as well as LDH‐induced mild hyperthermia and ion effects, thereby enabling “temporal regulation” treatment of osteosarcoma‐associated bone defects. This study provides a valuable insight for the development of osteosarcoma‐associated bone repair materials.