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

ABSTRACT 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.