A Nano-Strategy for Advanced Triple-Negative Breast Cancer Therapy by Regulating Intratumoral Microbiota.

Abstract

Intratumoral microbiota have been identified as a component of the tumor microenvironment that regulates the metastatic behavior of tumors. They serve not only as indicators of tumor pathology but also as potential drug targets in cancer therapy. Herein, a multifunctional nanoplatform (DD@FEL) is prepared by combining antibiotic doxycycline (DOXY) that can combat intratumoral microbiota and the chemotherapeutic drug doxorubicin (DOX) in ergosterol-originated liposome. Specially, ergosterol is utilized as a substitute for cholesterol in liposomes to exert pharmacological activity. Mechanistically, DD@FEL leveraged DOXY to inhibit cancer metastasis based on the regulation of intratumoral microbiota, which synergizes with the chemotherapeutic effect of DOX, eventually inhibiting the progression of triple-negative breast cancer (TNBC). Verified both <i>in vitro</i> and <i>in vivo</i>, DD@FEL effectively exerts a cytotoxic effect on TNBC cells, delays the growth of primary TNBC, and attenuates the development of its lung metastasis, providing a promising therapeutic strategy to control both orthotopic and metastatic TNBC.