Smart NIR-Light-Mediated Nanotherapeutic Agents for Enhancing Tumor Accumulation and Overcoming Hypoxia in Synergistic Cancer Therapy

The efficacy of photodynamic therapy (PDT) still shows limited success in clinical application due to hypoxia in the solid tumor, low tumor accumulation and limited light penetration depth of photosensitizers (PS). The previously reported MnO₂-based nanotherapeutic agents always required intratumoral injection or complex targeting modification process to improve the therapeutic efficacy. Herein, new MnO₂-based nanotherapeutic agents (honeycomb MnO₂/IR780/BSA nanoparticles, HMIB NPs) are designed and prepared to achieve excellent phototherapeutic performance characterized by NIR-light-mediation, deep diffusion via TME response and O₂ self-supply. The ex vivo and in vivo NIR fluorescence imaging results demonstrate that the honeycomb nanostructure of HMIB NPs facilitates the high tumor accumulation of hydrophobic IR780 via enhanced permeability and retention (EPR) effect after intravenous injection. The immunofluorescence results demonstrate that the TME response of HMIB NPs not only provides O₂ for relieving hypoxia but also reduces size for improving deep intratumoral diffusion. As a result, under the synergy of NIR fluorescence imaging, photothermal effect and PDT of IR780 with TME responsive size-change, and O₂ self-supply of honeycomb MnO₂, the HMIB NPs have achieved all-in-one NIR fluorescence and photothermal dual-model imaging guided synergistic PDT/PTT under a single-wavelength NIR light irradiation.