A lysosomal escape-enabled endoplasmic reticulum-targeting BODIPY photothermal agent for enhanced tumor ablation

Photothermal therapy (PTT) has emerged as a promising minimally invasive strategy for tumor treatment due to its high selectivity, minimal drug resistance, and precise controllability. However, the efficacy of PTT is often limited by the inability of photothermal agents (PTAs) to effectively target subcellular organelles after cellular uptake. In this study, we designed and synthesized an endoplasmic reticulum (ER)-targeting BODIPY-based photothermal agent (ER-BDP) by functionalizing a trifluoromethyl-substituted BODIPY scaffold with a p-toluenesulfonyl group. The resulting ER-BDP nanoparticles (ER-BDP NPs), co-assembled with DSPE-PEG₂₀₀₀-Biotin, exhibit excellent near-infrared absorption (λmax = 780 nm), high photothermal conversion efficiency (80.3%), and efficient tumor targeting via the enhanced permeability and retention (EPR) effect. Importantly, ER-BDP NPs demonstrate the ability to escape from lysosomes and specifically accumulate in the ER, where localized photothermal heating induces severe ER stress and apoptosis. In vitro and in vivo studies confirm that ER-BDP NPs effectively ablate tumor cells under mild laser irradiation (760 nm, 500 mW cm^-2) while showing negligible systemic toxicity. This work provides a rational design strategy for organelle-targeting photothermal agents and highlights their potential for enhanced tumor therapy.