Multifunctional nanoplatforms deciphering immune resistance in bone tumors: cooperative delivery, immune reprogramming and microenvironment remodeling

Bone tumors, encompassing primary sarcomas such as osteosarcoma and secondary skeletal metastases from carcinomas, present a stubborn clinical problem. Their treatment is hampered by three interconnected barriers: the physical impediment of a mineralized matrix that restricts drug access, a profoundly immunosuppressive microenvironment that inactivates antitumor immunity, and the lack of endogenous tissue regeneration following therapeutic intervention. Conventional modalities-including systemic chemotherapy, surgical resection, and even modern immunotherapies-often yield disappointing results against these complex lesions. In this context, nanotechnology offers a fresh therapeutic perspective. Engineered nanoplatforms are designed to home in on bone lesions, disrupt local immunosuppressive networks, and re-establish immunosurveillance. This review critically examines how these integrated systems counteract immune resistance. We focus on platforms that achieve precise bone targeting, reprogram the local immune landscape, and, crucially, coordinate the timing of tumor clearance with the process of functional bone repair. By tackling the dual challenges of immune evasion and structural defects, these multifunctional agents mark a significant departure from conventional approaches, holding the potential to simultaneously eradicate tumors and restore skeletal integrity.