“Dual lock-and-key” Triggered and Endoplasmic Reticulum Targeting Nanophotosensitizers for Activatable Type-I Photodynamic and Photothermal Therapies

Abstract

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 the inherent limitations of side effects caused by “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 nanophotosensitizerr for fluorescence imaging-guided activatable Type-I PDT and photothermal therapy (PTT). This “smart” nanophotosensitizer maintains an "off" state during systemic circulation, and specifically activated only in acidic and GSH-overexpressed TME ("on" state), where the fluorescence, ROS generation, and photothermal photothermal conversion capabilities were recovered, leading to precise and enhanced phototherapies in tumor sites with minimizing side effects. Sulfur-substituted and ER-targeting hemicyanine leads to a large red-shift absorption, concurrent Type-I ROS production and photothermal conversion on ER, thereby enhanced protein deactivation and ER stress. Comprehensive in vitro and in vivo investigations demonstrated that the TME dual triggered activatable nanophotosesitizer, upon NIR laser irradiation, effectively kill tumor cells, and significantly suppressing tumor growth by fluorescence imaging-guided Type-I PDT and PTT. This work provides a pathway for developing tumor microenvironment-triggered precise phototherapeutics with improved biosafety and clinical translation potential.