A borate-functionalized hypoxia-activatable theranostic agent for targeted tumor photo-chemoimmunotherapy

Hypoxia-activated theranostic agents (HATAs) represent a promising strategy for selective visualization and treatment of hypoxic tumor cells. However, their therapeutic efficacy is restricted by limited tumor-targeting capability, inefficient theranostic agent activation and immunosuppressive microenvironment. Herein, we report a borate-functionalized hypoxia-activatable theranostic agent (AHD-BA) and its application in targeted tumor photo-chemoimmunotherapy. This theranostic agent integrates a NIR-activatable photosensitizer (PS) and a chemotherapeutic drug via an arylazo linker, as well as a boronic acid ester (BAE) moiety that captures NADH to facilitate hypoxia-triggered drug release and significantly enhance tumor-targeting capability. AHD-BA undergoes azoreductase (AzoR)-mediated activation with significantly faster release kinetics compared to its BAE-lacking counterpart (AHD), enabling more efficient consumption of NADH and liberation of both chemotherapeutic agent and PS. Importantly, AHD-BA showed significantly enhanced (55.8-fold) NIR fluorescent intensity in tumor region than AHD. Furthermore, AHD-BA exerted significant anti-tumor effects via inducing mitochondrial dysfunction, mtDNA leakage and energy metabolism disruption, which activated apoptosis and pyroptosis via caspase-3 mediated pathways and ultimately potentiated robust anti-tumor immunity with negligible side effect. This work presents a uniform design strategy with the dual capability of enhancing hypoxia-activated theranostic agent release and enabling its tumor-targeted photo-chemoimmunotherapy.