EGCG and DOX dual-drug-loaded enzyme-responsive nanovesicles boost mitochondrial-mediated ICD for improved immunotherapy.

Enhancing cancer immunotherapy using methods that induce immunogenic cell death (ICD) can significantly improve its effectiveness and profoundly influence its role as a highly efficient cancer treatment strategy. However, the limited penetration of cytotoxic T cells into tumors, owing to dense tumor fibrosis, remains a significant barrier to immunotherapy. A tumor microenvironment-sensitive intelligent dual-drug delivery system was developed to simultaneously deliver epigallocatechin-3-gallate (EGCG) and doxorubicin (DOX) to mitochondria. EGCG enhanced the mitochondria-targeted action of DOX and increased damage to the mitochondrial electron transport chain which facilitated capturing electrons in the mitochondrial matrix of DOX. Subsequently, DOX molecules form a semiquinone intermediate and electrons are transferred to oxygen to generate reactive oxygen species (ROS) that induce mitochondrial apoptosis. These results indicate that EGCG amplifies the combined effects of chemo/chemodynamic therapy of DOX, demonstrating a pronounced synergistic ICD effect that recruits CD8