Self‐Adaptive Hydrogel with Cascade Microenvironments‐Responsiveness to Inhibit Osteosarcoma Progression and Augment Bone Reconstruction

Abstract Osteosarcoma (OS) is a highly aggressive and lethal malignant tumor with a 5‐year overall survival rate of less than 20%, while its post‐operative recovery remains suboptimal due to persistent inflammatory responses, incomplete clearance of residual tumor cells, and insufficient repair of tumor‐induced large bone defects. Herein, a self‐adaptive multi‐functional RPSH hydrogel is successfully prepared by integrating a self‐assembled 1‐bromoacetyl‐3,3‐dinitroazetidine (RRx‐001)/indocyanine green (ICG)@diselenide nanoparticle (R/I@SeNP) into a dual‐network polyacrylamide/sodium alginate/hyaluronic acid (PAAm/SA/HA) hydrogel matrix. Initially, high molecular weight HA effectively suppresses the NF‐κB pathway and induces macrophage polarization toward the M2 phenotype within 24 h, thereby reversing inflammatory microenvironments following OS resection. Then, dual‐responsive R/I@SeNP enables a multi‐modal anti‐cancer approach by up‐regulating levels of reactive oxygen/nitrogen species and generating RSeH or the immune checkpoint inhibitor RSeO(OH) with a tumor growth inhibition rate of 72.84% ± 6.75% at three weeks post‐surgery. Remarkably, the RPSH hydrogel promotes substantial new‐bone formation and achieves a bone volume/total tissue volume (BV/TV) ratio of 59.03% ± 9.41% following eight weeks of implantation by regulating the osteogenic‐osteoclastic balance, demonstrating its sustained ability to create microenvironments favorable for bone regeneration. This self‐adaptive hydrogel‐based strategy offers promising insights and potential benefits for improving post‐operative OS therapy.