Immune checkpoint-regulatable hydrogel-immobilized nanotherapeutics for post-surgical treatment of osteosarcoma

• Chemo-immunotherapy could revolutionize the treatment of osteosarcoma. • Gel-immobilized nanotherapeutics mitigate osteosarcoma recurrence and propagation. • The STING agonists result in the initiation of T cell-mediated immune responses. Osteosarcoma recurrence following surgical resection is notoriously prevalent and resistant to chemotherapy ( i.e. , doxorubicin, DOX) due to its intricate immunosuppressive tumor microenvironment, which remains one of the most life-threatening tumors. In this study, we report the fabrication of an in-situ injectable hydrogel-immobilized nanotherapeutics, tailored to stimulate tumoricidal immunity, thus mitigate both localized osteosarcoma recurrence and the propagation of metastatic tumors subsequent to surgical intervention. Zeolitic imidazolate framework-8 nanoparticles (ZIF NPs), encapsulating a chemotherapeutic agent ( i.e. , DOX) and immunotherapeutic agents ( i.e. , αPDL1 and αCD47), are loaded in fibrin hydrogels. These bioengineered constructs are judiciously deployed at surgical sites to orchestrate chemo-immunotherapeutic interventions, effectuated through the controlled release of doxorubicin and the initiation of T cell-mediated immune responses. DOX has the capability to eradicate tumor cells and initiate immunogenic cell death. Notably, αPDL1 engenders the circumvention of PDL1-mediated resistance and dominates metastatic tumor expansion, thereby exerting a pivotal role in the context of systemic immunosuppression. αCD47 blocks the 'don't eat me' signaling axis intrinsic to cancer cells, thereby potentiating their phagocytosis by macrophages. This orchestrated blockade synergistically activates the host immune milieu, thereby repressing tumor recurrence and curtailing the growth of metastatic lesions post-surgical resection in the subcutaneous tumor model (lateral and bilateral) and tibial tumor model (orthotopic and metastatic), respectively. Additionally, zinc ions from the degradation of ZIF NPs acts as the stimulator of interferon genes (STING) agonists to enhance the immunotherapeutic activity against distal and metastatic tumors. The reported immune checkpoint-regulatable cancer immunotherapy activates the host innate and adaptive immune systems, which shows promising for the treatment of osteosarcoma patients.