EGCG‐enabled Deep Tumor Penetration of Phosphatase and Acidity Dual‐responsive Nanotherapeutics for Combinatory Therapy of Breast Cancer

Abstract The presence of dense collagen fibers is a typical characteristic of triple‐negative breast cancer (TNBC). Although these fibers hinder drug penetration and reduce treatment efficacy, the depletion of the collagen matrix is associated with tumor metastasis. To address this issue, epigallocatechin‐3‐gallate (EGCG) is first exploited for disrupting the dense collagenous stroma and alleviate fibrosis by specifically blocking the TGF‐β/Smad pathway in fibroblasts and tumor cells when intraperitoneally administrated in TNBC tumor‐bearing mice. A methotrexate (MTX)‐loaded dual phosphate‐ and pH‐responsive nanodrug (pHA@MOF‐Au/MTX) is next engineered by integrating Fe‐based metal–organic frameworks and gold nanoparticles for improved chemo/chemodynamic therapy of TNBC. Surface modification with pH (low)‐insertion peptide substantially enhanced the binding of the nanodrug to 4T1 cells owing to tumor stroma remodeling by EGCG. High‐concentration EGCG inhibited glutathione peroxidase by regulating mitochondrial glutamine metabolism, thus facilitating tumor cell ferroptosis. Furthermore, sequential EGCG and pHA@MOF‐Au/MTX treatment showed remarkable anti‐tumor effects in a mouse model of TNBC, with a tumor growth inhibition rate of 79.9%, and a pulmonary metastasis rate of 96.8%. Altogether, the combination strategy developed in this study can improve the efficacy of chemo/chemodynamic therapy in TNBC and represents an innovative application of EGCG.