Hypoxia-responsive Exatecan prodrug liposomes co-delivered with IR808 for synergistic chemo-photodynamic therapy of breast cancer.

To overcome the poor solubility, rapid clearance, and systemic toxicity of Exatecan, we developed a tumor-activated liposomal delivery system co-encapsulating a hypoxia-cleavable Exatecan-squalene prodrug (EXA PRO) and the photosensitizer IR808. The nanocarrier integrates photodynamic therapy-induced hypoxia with bioreductive drug activation, enabling spatiotemporally controlled release within the tumor microenvironment. The liposomes, formulated with pH-sensitive lipids, exhibited uniform size (∼136 nm), high encapsulation efficiency, and dual responsiveness to acidic pH and reductive stress. Upon near-infrared laser irradiation, IR808 generated reactive oxygen species and aggravated intratumoral hypoxia, thereby triggering the cleavage of the azobenzene linker and facilitating targeted release of Exatecan. In vitro and in vivo studies confirmed enhanced cellular uptake, efficient intracellular drug release, potent tumor growth inhibition, and favorable biosafety profiles. This synergistic chemo-photodynamic strategy offers a promising platform for precise, tumor-selective drug delivery and represents a potential advancement in personalized cancer therapy.