Targeting Bone Tumor and Subcellular Endoplasmic Reticulum via Near Infrared II Fluorescent Polymer for Photodynamic‐Immunotherapy to Break the Step‐Reduction Delivery Dilemma

Specific localization of photosensitizers (PSs) to a certain organelle could result in targeted attack to cause greater trauma to cancer cells, eventually maximizing photodynamic therapy (PDT). However, currently, efficient and precise transportation of PSs via drug delivery to tumor cells and subcellular organelles is still challenging, due to a so‐called step‐reduction delivery dilemma (SRDD) which also threatens anticancer drug delivery to exert their efficacy. Herein, a cascade targeting near infrared II (NIR II) fluorescent nanoparticles (NP(ER/BO‐PDT)) is designed that can target bone tumor first and then target the subcellular organelle of endoplasmic reticulum (ER). It is found that NP(ER/BO‐PDT) achieves the targeted accumulation of the bone tumor and then ER. NP(ER/BO‐PDT) generates reactive oxygen species (ROS) in the subcellular organelles of ER under near infrared light irradiation. The continuous ER stress by ROS promotes the release of more damage‐associated molecular patterns, induces immunogenic cell death, stimulates the adaptive immune response, and further synergistically inhibits tumor growth, achieving the so‐called photodynamic‐immunotherapy. Overall, this study exemplifies a safe and efficient nano‐drug delivery system for a bone and ER cascade targeting via delivery of PSs to break the SRDD and highlights potential clinical translation.