Logic-gated approach for targeted delivery and site-selective activation of photothermal agents in precision cancer treatment.

Logic-gated strategies represent a promising approach to achieving highly selective cancer therapies. In this work, we present LG-AB (Logic-Gated Aza-BODIPY), an OFF-ON photothermal therapy (PTT) agent designed to selectively target cancer cells. LG-AB undergoes a red-shift in its maximum absorbance wavelength when activated in the tumor microenvironment, enabling the molecule to precisely generate heat in the cancerous tissue upon light irradiation. Unlike conventional activatable agents that rely on a single biomarker, LG-AB employs an AND logic-gated design, where glucose transporter 1 (GLUT1) overexpression facilitates targeted cellular uptake in cancer cells, followed by activation through elevated glutathione (GSH) levels. Beyond demonstrating photothermal efficacy in human lung cancer and murine breast cancer cells, we show that LG-AB effectively attenuates cancer progression through heat-induced apoptosis, with minimal off-target effects to surrounding tissues. The versatility of this strategy is further demonstrated through the development and application of LG-CPT (Logic-Gated Camptothecin), which utilizes the same logic-gated design. Our results show that enhancing specificity and limiting collateral damage can be broadly applied across different therapeutic agents.