Development of a Hypoxia-Triggered Supramolecular Nanoplatform for Synergistic Hypoxia Alleviation and Amplified Photodynamic Cancer Therapy

Photodynamic therapy (PDT) represents a highly promising modality for cancer treatment; however, its clinical success is significantly restricted by the hypoxic nature of the tumor microenvironment (TME). Hypoxia also upregulates hypoxia-inducible factor-1α (HIF-1α) expression, thereby exacerbating tumor malignancy. To tackle this challenge, we engineered a hypoxia-activatable supramolecular nanoplatform (GH@CyNPs) capable of dual hypoxia reversal and amplification of PDT efficacy. The nanoplatform was constructed via host–guest interactions between a water-soluble pillar[5]arene (WP5) and an azobenzene-linked cyanine/YC-1 conjugate (Cy-G), followed by the co-encapsulation of glucose oxidase (GOx) and catalase (CAT). Upon entering the cancer cells via endocytosis, the azobenzene linker is specifically cleaved by the hypoxic TME, facilitating payload release. Concurrently, the released GOx/CAT pair drives in situ cascade reactions to generate oxygen (O2), while YC-1 effectively suppresses HIF-1α expression, thereby achieving synergistic alleviation of hypoxia. Under irradiation, the released cyanine acts as a potent photosensitizer, generating abundant reactive oxygen species (ROS) to kill cancer cells. Both in vitro and in vivo evaluations corroborated that GH@CyNPs exhibit preferential tumor accumulation, profound antitumor efficacy, and excellent biocompatibility. This study presents an innovative paradigm for overcoming TME hypoxia to optimize photodynamic oncotherapy.