“Dual lock-and-key” triggered and endoplasmic reticulum targeting nanophotosensitizers for activatable Type-I photodynamic and photothermal therapies

Photodynamic therapy (PDT) has emerged as a critical modality in cancer treatment with the merits of non-invasiveness, spatiotemporal control, and minimal drug resistance. However, the clinical application of PDT is often hindered by inherent limitations, including side effects caused by the "always on" state of reactive oxygen species (ROS) and low ROS generation efficiency in hypoxic tumors. To overcome these limitations, we developed a tumor microenvironment (TME) "dual lock-and-key" triggered and endoplasmic reticulum (ER) targeting nanophotosensitizer for fluorescence imaging-guided activatable Type-I PDT and photothermal therapy (PTT). This "smart" nanophotosensitizer remains in an "off" state during systemic circulation, and is specifically activated only in the acidic and GSH-overexpressed TME ("on" state), where its fluorescence, ROS generation, and photothermal conversion capabilities are restored, leading to precise and enhanced phototherapies at tumor sites while minimizing side effects. Sulfur-substituted and ER-targeting hemicyanine induces a large red-shift in absorption, simultaneously generating Type-I ROS and producing a photothermal effect in the ER, thereby enhancing protein deactivation and ER stress. Comprehensive <i>in vitro</i> and <i>in vivo</i> investigations demonstrated that the TME dual triggered activatable nanophotosensitizer, upon NIR laser irradiation, effectively kills tumor cells, and significantly suppresses tumor growth through fluorescence imaging-guided Type-I PDT and PTT. This work provides a pathway for developing TME-triggered precise phototherapeutics with improved biosafety and potential for clinical translation.