Cascade-activatable nanotheranostics for near-infrared fluorescence imaging-guided photoimmunotherapy

Activatable photoimmunotherapeutic systems have emerged as effective tools for cancer treatment. However, currently reported systems have difficulty achieving both a high activation rate and high selectivity. Herein, a glutathione (GSH)-responsive theranostic nanoparticle, CSJ@BMP, is reported for combined photoimmunotherapy with both high activation efficiency and selectivity. CSJ@BMP is co-assembled from a methylene blue (MB)-based, biotin receptor-targeting responsive amphiphilic polymer (BMP) and a prodrug (CSJ), which is synthesized by conjugating the chemotherapeutic agent chlorambucil (Cbl) with the programmed cell death ligand 1 (PD-L1) inhibitor JQ-1 through a singlet oxygen (¹O₂)-cleavable linker. Upon sequential triggering by high GSH concentrations and near-infrared (NIR) light, the nanoparticles undergo structural disintegration through the reaction between the activated drugs (Cbl-SH and JQ1-SH) and BMP, leading to the self-amplified release of MB, Cbl-SH, and JQ1-SH. In addition, such process does not occur under low GSH concentrations, ensuring high selectivity towards tumor tissue. The released drugs trigger immunogenic cell death (ICD) through combined chemo and photodynamic therapy and activate immune responses to inhibit primary, distant, and metastatic tumors. Thus, this study presents an activatable nanosystem with high tumor selectivity and photo-enhanced activation for cancer photoimmunotherapy with reduced side effects. SYNOPSIS: This study reported an activatable therapeutic nanoparticle (CSJ@BMP) that can achieve cascade-combined self-amplified activation for NIR-I fluorescence imaging-guided cancer photoimmunotherapy. The activation of CSJ@BMP can achieve complete release of active drugs with high GSH selectivity. It not only solves the disadvantage of incomplete activation for responsive nanomedicines, but also owns high specificity towards tumor tissue.