Mn(III)-porphyrin/hyaluronic acid nanoparticles for enhanced sonodynamic/chemodynamic synergistic therapy via remodeling tumor reductive microenvironment

Sonodynamic therapy (SDT) and chemodynamic therapy (CDT) are frequently constrained by the elevated redox levels within the tumor microenvironment. Ingeniously designed nanoparticles that enhance the efficacy of sonodynamic/chemodynamic synergistic therapy by remodeling tumor microcirculation represent effective strategies. Herein, we developed drug-loaded nanoparticles (HBMD NPs) capable of remodeling the tumor microenvironment (TME), which were constructed through self-assembly of cyclodextrin-modified Mn(III)-porphyrin and hyaluronic acid (HA) derivatives. The Mn(III)-porphyrin encapsulated within the nanoparticles depletes endogenous glutathione (GSH), thereby effectively inhibiting the scavenging of reactive oxygen species (ROS) generated by CDT and SDT. This thereby significantly enhances the therapeutic efficacy of combined CDT and SDT against breast cancer. HA functions as an endogenous self-targeting carrier, significantly prolonging the systemic circulation of nanoparticles and amplifying their accumulation in CD44-overexpressing tumor cells. Upon reaching the acidic tumor microenvironment, the nanoparticles rapidly disintegrate and release the metalloporphyrin. The HBMD NPs displayed satisfactory Fenton catalytic properties and a strong GSH depleting function, demonstrating significant cytotoxicity toward cancer cells and efficient tumor inhibition. This work expands the potential clinical applications of combined SDT/CDT for cancer treatment by remodeling the tumor reductive microenvironment.