Functionalized Photoimmune Hydrogel Microspheres for Inside‐Out Eradication of Osteosarcoma via a PD‐L1 PROTAC Strategy

Immunotherapy has demonstrated promising potential for tumor suppression; however, effectively reversing the immunosuppressive microenvironment in osteosarcoma remains challenging. Herein, we developed an immunogel microsphere, CP-MOF@gel, capable of precise PD-L1 protein degradation. This system is based on core-shell nanoparticles with an amorphous ZIF-8 shell encapsulating the photosensitizer Cypate and a proteolysis-targeting chimera (PROTAC) molecule ppd (PROTAC PD-L1 degrader), followed by microfluidic and photocuring processes. The synthesis conditions of the CP-MOF are optimized to enhance drug loading and reduce particle size. Acting as a Trojan horse, CP-MOF@gel enables the sustained release of the vanguard CP-MOFs in osteosarcoma. Once internalized by tumor cells, some CP-MOFs generate reactive oxygen species (ROS) and induce photothermal effects under irradiation, triggering pyroptosis through a caspase-1/gasdermin D (GSDMD)-dependent pathway and activating the antitumor immunity. Meanwhile, extracellular CP-MOFs facilitate precise PD-L1 degradation via ppd, thereby enhancing T-cell-mediated tumor cell killing. In vivo studies revealed effective tumor retention of CP-MOF@gel, significantly improving immunotherapy outcomes in osteosarcoma. This work establishes a precision PROTAC-based protein degradation strategy to suppress osteosarcoma and introduces an 'inside-out' therapeutic approach for reversing the immunosuppressive tumor microenvironment.