Charge-Reversal Polymeric Nanomodulators for Ferroptosis-Enhanced Photodynamic Therapy

Abstract

The clinical application of photodynamic therapy (PDT) faces some limitations including poor tumor targeting properties, high reductive tumor microenvironment, and inefficient activation of single cell death machinery. We herein report pH-sensitive polymeric nanomodulators (NBS-PDMC NPs) for ferroptosis-enhanced photodynamic therapy. NBS-PDMC NPs were constructed by the positively charged type-I photosensitizer (NBS) coordinated with the demethylcantharidin (DMC)-decorated block copolymer via electrostatic interaction. NBS-PDMC NPs had a negative surface charge, which ensures their high stability in bloodstream circulation, while exposure to lysosomal acidic environments reverses their surface charge to positive for tumor penetration and the release of DMC and NBS. Under the NIR light irradiation, NBS generated ROS to induce cell damage, in the meantime, DMC inhibited the expression of GPX4 protein in tumor cells and promoted ferroptosis of tumor cells. This polymer design concept provides some novel insights into smart drug delivery and combinational action to amplify the antitumor effect.