Enhanced Cerenkov radiation induced photodynamic therapy based on GSH-responsive biomimetic nanoplatform to trigger immunogenic cell death for tumor immunotherapy

Cerenkov radiation (CR) can serve as a source of internal light to overcome the limited tissue penetration of external light in conventional photodynamic therapy (PDT). However, insufficient luminescence intensity hinders the clinical application of CR-PDT. Here, we developed a glutathione-responsive biomimetic nanoplatform by fusing cancer cell membranes and liposomes loaded with photosensitizer hematoporphyrin monomethyl ether (HMME) and a radiation energy amplifier Eu³⁺, named HMME-Eu@LEV. Colloidal Eu³⁺ converts γ-radiation and CR from radioisotopes into fluorescence to enhance anti-tumor effects. Sequential administration ensures co-localization of HMME-Eu@LEV and radiopharmaceutical ¹⁸F-fluorodeoxyglucose (FDG) at the tumor site, triggering enhanced CR-PDT and immunogenic cell death. Our observations indicated that luminescence resonance energy transfer between Eu³⁺ and HMME was efficient, and Cerenkov luminescence from Eu@LEV+FDG was approximately 5.6-fold higher in intensity than that from FDG alone. As a result, abundant ROS were generated, and macrophages in the tumor microenvironment were polarized from M2 to M1. In addition, the immunosuppressive tumor microenvironment could be reversed by promoting the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes. The activated immune system effectively inhibited the growth of primary tumors and spread of distant metastases. Our work demonstrates the feasibility of CR-PDT without an external light source and the critical role of nanomaterials in personalized medicine.