Nanoradiosentizers with X Ray-Actuatable Supramolecular Aptamer Building Units for Programmable Immunostimulatory T Cell Engagement

The insufficient activation and impaired effector functions of T cells in the immunosuppressive tumor microenvironment (TME) substantially reduces the immunostimulatory effects of radiotherapy. Herein, a multifunctional nanoradiosensitizer is established by integrating molecularly engineered aptamer precursors into cisplatin-loaded liposomes for enhancing radio-immunotherapy of solid tumors. Exposure to ionizing radiation (IR) following the nanoradiosensitizer treatment would induce pronounced immunogenic death (ICD) of tumor cells through cisplatin-mediated radiosensitization while also trigger the detachment of the aptamer precursors, which further self-assemble into PD-L1/PD-1-bispecific aptamer-based T cell engagers (CA) through the bridging effect of tumor-derived ATP to direct T cell binding onto tumor cells in the post-IR TME in a spatial-temporally programmable manner. The CA-mediated post-IR tumor-T cell engagement could override the immunosuppressive barriers in TME and enhance T cell-mediated recognition and elimination of tumor cells while minimizing systemic toxicities. Overall, this work offers an innovative approach to enhance the radio-immunotherapeutic efficacy in the clinics.