A multimodal imaging-guided nanoreactor for cooperative combination of tumor starvation and multiple mechanism-enhanced mild temperature phototherapy

Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), has shown great promise for cancer treatment in many preclinical studies. This study reports a nanoreactor designed for an enhanced mild temperature phototherapy which utilizes multiple mechanisms including simultaneous glucose consumption, oxygen supply, glutathione (GSH) depletion and heat-resistance relief. The nanoreactor is prepared using an Fe-doped polydiaminopyridine (Fe-PDAP) nanozyme with an intrinsic catalase-like activity coloaded with glucose oxidase (GOx) and indocyanine green (ICG). Evidence shows that glucose plays a vital role in tumor progression. Initiated by the breakdown of glucose into gluconic acid and H2O2 by GOx, Fe-PDAP promotes reoxygenation by catalyzing the reaction-supplied and tumor cell-supplied H2O2 into O-2, which then enhances the O-2-dependent PDT. Moreover, Fe-PDAP depletes GSH in tumor cells for more efficient reactive oxygen species (ROS) production. Meanwhile, the heat resistance of tumor cells is relieved by GOx-induced glucose exhaustion and heat shock protein (HSP) reduction, improving the efficiency of PTT. In particular, the nanoreactor also serves as a contrast agent for fluorescence, photoacoustic, and magnetic resonance multimodal imaging. Consequently, this nanoreactor efficiently inhibits tumor growth through mild temperature phototherapy under multimodal imaging guidance, resulting in successful tumor ablation with minimal systemic toxicity.