A sonogenetic antigen-presenting nanoplatform enables spatiotemporal control of calcium signalling in T cells for enhanced cancer immunotherapy.

Abstract

Effective T-cell activation plays the critical role in cancer immunotherapy; however, strategies to precisely and sustainably stimulate antitumor T-cell responses while minimizing systemic toxicity remain limited. Here, we develop a sonogenetic artificial antigen-presenting cell (aAPC) platform for remote, spatiotemporally controlled Ca2+ influx in tumor-infiltrating T cells. The platform consists of poly (lactic-co-glycolic acid) nanoparticles loaded with the plasmid encoding the Mechanosensitive channel of large conductance (MSCL), coated with tumor-pulsed dendritic cell membranes to provide costimulatory signals, and conjugated with PD-1-targeting aptamers for T-cell-specific delivery. The nanoplatform exhibited high gene transfection efficiency within T cells and realize the expression of US (US)-responsive MSCL on the surface of T cells. Upon US irradiation, the engineered MSCL open, triggering controlled Ca2+ influx and activating downstream NFAT signalling. Therefore, sonogenetic aAPC results in the efficient and specific synergistic activation of T cells, improves the killing effects of T cells and ameliorated the dysfunction of exhausted T cells. In B16-F10 melanoma-bearing mice, sonogenetic aAPC promotes tumor infiltration and proliferation of CD8+ T cells, reduces immunosuppressive cells, and significantly suppresses tumor growth without eliciting adverse systemic immune-related events. This work demonstrates a safe and effective strategy for remotely potentiating T-cell-mediated antitumor immunity through precise sonogenetic control of calcium signalling.