Nano-Optogenetic Engineering of CAR T-cells for Precision Immunotherapy with Enhanced Safety

FDA-approved chimeric antigen receptor (CAR) T cell-based immunotherapy has shown curative potential in patients with hematological malignancies. However, owing to the lack of control over the location and duration of anti-tumor immune response, CAR T-cell therapy still faces significant safety challenges arising from cytokine release syndrome and on-target off-tumor toxicity. Herein, we present the design of light-switchable CAR T-cells (designated “LiCAR-T”) that allow real-time photo-tunable activation of therapeutic T cells to precisely induce tumor cell killing. When coupled with imaging-guided, surgically removable upconversion nanoplates (UCNPs) that have enhanced near infrared (NIR)-to-blue upconversion luminescence as miniature deep tissue photon-transducers, LiCAR T-cells enable both spatial and temporal control over T cell-mediated anti-tumor therapeutic activity in vivo with greatly mitigated side effects. Our nano-optogenetic immunomodulation platform not only provides a unique approach to interrogate CAR-mediated anti-tumor immunity, but also sets the stage for developing precision medicine to deliver personalized anti-cancer therapy.