A Hypoxia‐Triggered Bioreduction of Hydrophilic Type I Photosensitizer for Switchable In Vivo Photoacoustic Imaging and High‐Specificity Cancer Phototherapy

Abstract Considering that hypoxia is strongly connected with tumor proliferation, metastasis, invasion, and drug resistance, it is of significant implication for alleviating the effects of hypoxia in tumor treatment. The negligible oxygen‐dependent nature of type I photosensitizers (PSs) has made them appropriate candidates for the treatment of hypoxic tumors. However, the lack of effective molecular design approaches, the phototoxicity of PSs to normal tissue before and after treatment, and the drawbacks of poor hydrophilicity severely hinder the development of PSs in hypoxic tumor therapy. Thus, developing a hydrophilic PS with good hypoxia resistance and minimal side effects is an urgent but challenging problem. Herein, we present a nanotheranostic ( NanoPcN8O ) based on the self‐assembly of a hydrophilic phthalocyanine derivative ( PcN8O ), a hypoxia‐responsive bioreductive phototherapeutic agent suitable for activatable photoacoustic (PA) imaging and tumor therapy. Hypoxic regions in various tumors exhibit strong reductive capability, and only in such conditions did NanoPcN8O feature multiple N ‐oxide groups that could be bioreduced to yield the product NanoPcN8 with abundant electron‐rich tertiary amine groups, which switches on the type I photodynamic and photothermal effects, facilitating the generation of type I reactive oxygen species (ROS) and heat. Better still, NanoPcN8O achieved hypoxia‐induced selective PA imaging in a preclinical model. Based on these merits, the hypoxia‐induced switchable type I photodynamic therapy (PDT) and photothermal therapy (PTT) strategies demonstrated remarkable phototherapeutic efficiency with high biosafety. This delicate design is anticipated to offer a novel and safe strategy to overcome hypoxia resistance in phototherapeutics.