A programmable nanoreactor for photothermal immunotherapy via NIR-II triggered enzyme-catalyzed immunogenic tumor microenvironment remodeling

Abstract

The complicated and immunosuppressive tumor microenvironment usually obstruct the efficiencies of various therapeutic schedules including immunotherapy. Here, we report a programmable polymer-based nanoreactor for photothermal-enhanced immunotherapy through second near-infrared (NIR-II) light-triggered enzyme‑catalyzed immunogenic tumor microenvironment remodelling. The nanoreactor system contains a thermal-responsive liposome modified on its surface with xanthine oxidase (XO), and a core co-loaded with a NIR-II-absorbing semiconducting polymer, an oxygen carrier perfluorohexane (PFH) and a hypoxanthine substrate. Under NIR-II laser irradiation, the semiconducting polymer (SP-II) generates a local photothermal effect, directly ablating tumor cells and triggering a phase transition of the liposome shells, enabling precise pulsed release of the loaded contents. The released PFH rapidly alleviates local tumor hypoxia, providing a key substrate for subsequent enzyme cascade reactions. Simultaneously, hypoxanthine is catalyzed by XO to continuously generate superoxide anions and uric acid. In this approach, superoxide anions acting as reactive oxygen species enhance immunogenic cell death and oxidative stress, while uric acid serves as an endogenous danger signal, promoting M2 to M1 repolarization of tumor-associated macrophages, thereby synergistically remodeling the immunosuppressive tumor microenvironment. This strategy potently inhibits laser-irradiated primary tumors, as well as significantly suppresses the progress of distant and metastatic tumors, and prolongs the survival of mouse. Our study provides a new approach for developing programmable anti-tumor nanoreactors with enzyme-catalyzed immunogenic tumor microenvironment remodelling capabilities.