Hypoxia-Responsive Nano-Photosensitizer Anchored by PEGylated BODIPY: A Single-Laser-Driven Platform for Photo-Enhanced Synergistic Chemo/Photodynamic/Photothermal Cancer Therapy

The integration of chemotherapeutic drugs and photosensitizers into nanocarriers holds great potential for combining chemotherapy and phototherapy while reducing systemic toxicity. However, therapeutic efficacy is hindered by the hypoxic tumor microenvironment and the insufficient drug release. This study designs a multifunctional nano-photosensitizer BAP by conjugating hydrophobic boron dipyrromethene (BODIPY) with hydrophilic poly(ethylene glycol) via hypoxia-responsive azobenzene linkers. In aqueous media, BAP demonstrates self-assembly into stable nanoparticles (termed BAP NPs) that exhibit dual phototherapeutic functionalities. BAP NPs can be activated by single wavelength laser irradiation to initiate both photodynamic therapy (PDT) and photothermal therapy (PTT). The engineered BAP NPs further integrate dual-mode imaging capabilities, enabling fluorescence and photothermal imaging for nanocarrier visualization. To enhance antitumor efficacy, the chemotherapy doxorubicin (DOX) was further loaded into BAP NPs, forming nanomedicine BAP-DOX NPs. As expected, the azobenzene linkers of BAP are sensitive to the overexpressed azoreductase in hypoxic cancer cells, facilitating BAP disassembly and DOX release. Upon laser irradiation, the BAP component in BAP-DOX NPs eradicates superficial oxygen-rich tumor cells through PDT and PTT. PDT-caused oxygen consumption triggers acute hypoxia, enhancing DOX release in hypoxic tumor cells. Both in vitro and in vivo studies have demonstrated that BAP-DOX NPs exhibit remarkable antitumor activity through synergistic light-driven PDT/PTT and hypoxia-responsive chemotherapy. This research establishes an innovative therapeutic strategy to overcome hypoxia-induced therapeutic resistance through a simple photosensitizer-based nanocarrier that enables photo-enhanced drug release and synergistic chemo/photodynamic/photothermal tumor ablation.