Spatiotemporally Controlled Prodrug Release From Light-Triggered Azo-Bond-Cleaved BODIPY Nanoplatform for Trimodal...

Chemotherapy (CT) suffers from poor selectivity and systemic toxicity, while photodynamic therapy (PDT) and photothermal therapy (PTT) are inherently limited by tumor hypoxia and thermoresistance. Herein, we develop a trimodal synergistic nanoplatform (PDM-BDP NPs) for ovarian cancer treatment by integrating PDT, mild PTT (mPTT), and CT into a single azo-bond-linked prodrug system. Upon 808 nm laser irradiation, PDM-BDP NPs generate reactive oxygen species and mild hyperthermia, while simultaneously triggering azo-bond cleavage to release the chemotherapeutic agent phenylenediamine mustard (PDM) and transform into NH₂-BDP, which retains photothermal activity for sustained thermal output. PDM-BDP NPs exhibit efficient cellular uptake, predominant mitochondrial co-localization, and potent photocytotoxicity against A2780 cells with low dark toxicity. Transcriptomics reveals multi-target reprogramming involving proteotoxic stress, DNA damage, and TNF/MAPK activation. Laser-activated PDM-BDP NPs achieve subtotal tumor ablation with excellent biocompatibility. This trimodal synergistic strategy provides a promising approach for precise ovarian cancer therapy.