<p>Osteosarcoma faces the challenges of limited drug delivery and an immunosuppressive tumor microenvironment. M1 macrophages, a type of tumor-associated macrophage, play a pivotal role in shaping tumor immune responses. A dual enzyme–mimicking nanozyme coordinated to risedronate sodium and encapsulated in a sodium alginate gel (RZRSA) was developed to enhance the radiosensitivity of osteosarcoma. After intratumoral injection, RZRSA formed a calcium alginate hydrogel in osteosarcoma owing to the presence of Ca²⁺. Because of its peroxidase-like activity, RZRSA generated abundant toxic hydroxyl radicals in the presence of intratumoral H₂O₂ overexpression. Moreover, the hypoxia status of tumors was alleviated by the catalase-mimicking property of RZRSA by transforming H₂O₂ into O₂, thereby improving the efficacy of radiotherapy. The Ru elements in RZRSA augmented the energy decomposition of ionizing irradiation in tumor regions. These properties contributed to magnifying the oxidative stress in the tumor microenvironment, which promoted M1-like polarization to kill tumor cells. In addition, radiosensitization by RZRSA triggered a robust immunogenic cell death effect and promoted dendritic cell maturation. This innovative design of RZRSA provides a promising strategy for targeted osteosarcoma treatment.</p> Graphical Abstract <p></p>