Membrane-Bound Multimodal Plasmonic Transducers for Noninvasive, In Situ Monitoring and Control of CAR T Cells Against Heterogeneous Solid Tumors.

Abstract

Noninvasive monitoring and control of CAR T cells against heterogeneous solid tumors remain major challenges in understanding and improving treatment response. To address this, membrane-bound plasmonic transducers, composed of plasmonically coupled gold nanospheres in an anisotropic framework, were developed for multimodal photoacoustic imaging and localized thermal modulation of CAR T cell activity. These transducers exhibit approximately 90% absorption efficiency and photostability under laser fluences exceeding 20 mJ cm^-2, delivering photoacoustic and thermal responses over multiple lasing cycles. Membrane-bound transducers on CAR T cells thus enable photoacoustic and thermal responsiveness upon laser excitation without compromising key cellular functions. In heterogeneous HER2-expressing breast tumor models, longitudinal photoacoustic imaging enabled prospective stratification of tumors based on early T cell trafficking, predicting responders versus nonresponders with high sensitivity and specificity. Moreover, transducer-mediated thermal modulation of intratumoral CAR T cells engineered with thermogenetic circuits to secrete T cell engagers redirected cytotoxicity toward antigen-negative tumors, overcoming antigen escape and consequently enhancing therapy. Taken together, we demonstrate a strategy to noninvasively monitor and control CAR T cells against heterogeneous solid tumors via membrane-bound multimodal transducers.