A cyclic nano-reactor achieving enhanced photodynamic tumor therapy by reversing multiple resistances

Photodynamic therapy (PDT) is a clinically implemented modality to combat malignant tumor, while its efficacy is largely limited by several resistance factors from tumor microenvironment (TME), such as hypoxia, anti-oxidant systems, and ATP-dependent tumor adaptive resistances. The aim of this work is to construct a multifunctional nanoplatform to remodel multiple resistant TME for enhanced PDT.

Here, a targeting nano-reactor was facilely constructed to reverse the multiple resistances of PDT by incorporating glucose oxidase (GOx) and chlorin e6 (Ce6) into poly (D, L-lactic-co-glycolic acid) (PLGA)/ metal-organic framework (MOF) core-shell nanoassembly, with surface deposition of hyaluronic acid (HA) stabilized MnO₂. The nano-reactor could selectively target tumor cells by virtue of surface HA modification, and once internalization, a few reactions were initiated to modulate TME. Glucose was consumed by GOx to inhibit ATP generation, and the produced H₂O₂ was catalyzed by MnO₂ to generate O₂ for tumor hypoxia alleviation and photodynamic sensitization, and glutathione (GSH) was also effectively depleted by MnO₂ to suppress the tumor antioxidant defense. Consequently, the nano-reactor achieved robust PDT with amplified tumor therapy via intravenous injection.

This nano-reactor offers a multifunctional nanoplatform to sensitize TME-limited tumor treatment means via reversing multiple resistances.