Vacancy Engineering to Regulate Photocatalytic Activity of Polymer Photosensitizers for Amplifying Photodynamic Therapy against Hypoxic Tumors

Polymer photosensitizers (PPSs) with the distinctive properties of good light-harvesting capability, high photostability, and excellent tumor retention effects have aroused great research interest in photodynamic therapy (PDT). However, their potential translation into clinic was often constrained by the hypoxic nature of tumor microenvironment, the aggregation-caused reduced production of reactive oxygen species (ROS), and the tedious procedure of manufacture. As a powerful and versatile strategy, vacancy engineering possesses the unique capability to effectively improve the photogenerated electron efficiency of nanomaterials for high-performance O₂ and ROS production. Herein, by introducing vacancy engineering into the design of PPSs for PDT for the first time, we synthesized a novel PPS of Au-decorated polythionine (PTh) nanoconstructs (PTh@Au NCs) with the unique integrated features of distinguished O₂ self-evolving function and highly efficient ROS generation for achieving the greatly enhanced PDT efficacy toward hypoxic tumor both in vitro and in vivo. The incorporation of Au into PTh leads to the special PTh-Au heterostructure-induced sulfur vacancies in PTh@Au NCs, which results in an efficient electron-hole separation performance and also plays a key role in a long lifetime of free electrons and holes. Accordingly, an ∼2- to 3-fold ROS generation and an ∼1.5-fold increase of O₂ self-supply than the pure PTh nanoparticles (NPs) were obtained even under hypoxic conditions upon exposure to 650 nm light. By combining such superior ROS generation and O₂ self-supply performances with the outstanding cellular internalization and tumor accumulation capacities, an advanced antitumor effect with the achievement of almost complete hypoxic tumor elimination in vivo or 88% cell destruction in vitro was acquired by the PTh@Au NCs. In addition, the distinctive facile one-step redox strategy for PTh@Au NCs synthesis compared to the reported PPSs for PDT also makes it beneficial for potential practical application. The first introduction of vacancy engineering concept into PPSs in the field of PDT proposed in this work offers a new strategy for the development and design highly efficient PPSs for PDT applications.