A protease-activated plasmonic nanosensor for noninvasive photoacoustic monitoring of antitumor responses to adoptive T cell therapy

Adoptive T cell therapy (ACT) leverages patient’s own T lymphocytes to treat cancer, but noninvasive methods to assess therapeutic responses remain limited. We present a protease-activated plasmonic photoacoustic (PA) nanosensor for monitoring of in vivo cytotoxic T cell activity following ACT. The nanosensor, comprising a gold nanosphere functionalized with peptides responsive to granzyme B (GzmB, a protease secreted by activated cytotoxic T cells), aggregates upon GzmB exposure. This aggregation enhances near-infrared light absorption through plasmon coupling, producing strong PA signals. The nanosensor shows high specificity for GzmB over other proteases and correlates PA signal increases with antigen-specific T cell cytotoxicity in vitro. In murine ACT models, systemically administered nanosensors generate enhanced PA signals in target tumors, preceding measurable tumor volume changes. The platform’s peptide-tunable design enables adaptation to various protease targets, offering a broadly modular strategy for functional imaging in cancer and other immune-related diseases.