Metal-based photosensitizers are of great interest in photodynamic therapy (PDT) due to their tunable photophysicochemical characteristics and structure flexibility. Herein, an iridium-based photosensitizer (1) with a long-lived intraligand (3IL) excited state has been designed and synthesized, which shows significantly enhanced singlet oxygen (1O2) generation efficiency (∼45 folds) relative to that of the model iridium­(III) complex (2) under 460 nm irradiation. In order to achieve deep tissue penetration, complex 1 was further covalently bonded to the upconversion nanoparticles (UCNPs). Besides, 1-benzyl-3-(5′-hydroxymethyl-2′-furyl)­indazole (YC-1), an effective HIF-1α inhibitor, was physically adsorbed into the hydrophobic layer at the surface of UCNPs. Once upon near-infrared (NIR) irradiation, iridium complex 1-mediated toxic 1O2 was generated for PDT, whose efficient conversion of oxygen to 1O2 during the PDT would exacerbate the hypoxic condition of tumor tissue and lead to the upregulation of HIF-1α for the following HIF-1 targeting tumor therapy. This study highlights the potential for applying a nanoplatform composed of a long-lived iridium-based photosensitizer and an HIF-1α inhibitor in tumor therapy, which converts PDT-induced tumor hypoxia to a therapy advantage, thus opening up ideas to overcome the hypoxia in PDT therapy.

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