Ultrasound-activated biomimetic nanobubbles achieve synergistic immunotherapy by tumor cell membrane-based vaccination and PD-L1 PROTAC degradation.

Tumor vaccines can induce tumor-specific T cell responses to suppress tumor growth and prevent recurrence. However, their efficacy is substantially limited by the immunosuppressive tumor microenvironment, particularly PD-L1 overexpression, which impairs dendritic cell function and promotes T cell exhaustion. While anti-PD-L1 antibodies are used clinically, their effectiveness is constrained by poor tumor penetration, incomplete target occupancy, and acquired resistance. To address these challenges, this study explores a new paradigm of synergistic immunotherapy that combines a tumor cell membrane (TCM)-based vaccine with degradation of PD-L1. Specifically, TCMs are engineered into nanobubbles (NBs) to serve as a self-delivering nanovaccine platform, enabling codelivery of proteolysis-targeting chimera (PROTAC) designed to degrade PD-L1, resulting in the formation of a delivery system designated as TCM-NBs@PRO. Subsequently, ultrasound-triggered cavitation is integrated to facilitate efficient co-delivery of the vaccine components and PROTAC, thereby enhancing the overall efficacy of tumor immunotherapy. Experimental results demonstrate that TCM-NBs@PRO-mediated PD-L1 degradation significantly enhances CD8+ T cell infiltration and antitumor activity, while establishing durable protective immunity. By synergizing ultrasound-enhanced delivery, PROTAC-mediated PD-L1 depletion, and nanovaccine-driven T cell activation, this system overcomes the limitations of traditional vaccines and represents a promising approach for tumor immunotherapy with substantial clinical translational potential.