Membrane Fusion Liposomes Deliver Antifibrotic and Chemotherapeutic Drugs Sequentially to Enhance Tumor Treatment Efficacy by Reshaping Tumor Microenvironment.

The intricate tumor microenvironment in triple-negative breast cancer (TNBC) hampers chemotherapy and immunotherapy efficacy due to dense extracellular matrix (ECM) by tumor-associated fibroblasts (TAFs). Nanoparticle-based therapies, especially "all in one" nanoparticles, have shown great potential in combined drug delivery strategies to reshape the tumor microenvironment and enhance therapeutic efficiency. However, these "all in one" nanoparticles suffer from limitations in targeting different target cells, uncontrollable dosing ratio, and disregarding the impact of delivery schedules. This study prepared cell membrane fusion liposomes (TAFsomes and CCMsomes) to load FDA-approved anti-fibrotic drug pirfenidone (PFD/TAFsomes) and anti-tumor drug doxorubicin (DOX/CCMsomes). These liposomes can specifically target TAFs cells and tumor cells, and combined administration can effectively inhibit TAF activity, reshape the TME, and significantly enhance the tumor chemotherapy efficacy. Combined drug delivery defeats "all in one" liposomes (DOX/PFD/Liposomes, DOX/PFD/TAFsomes, and DOX/PFD/CCMsomes) by flexibly adjusting the drug delivery ratio. Moreover, an asynchronous delivery strategy that optimizes the administration schedule not only further improves the therapeutic effect, but also amplifies the effectiveness of α-PD-L1 immunotherapy by modulating the tumor immune microenvironment. This delivery strategy provides a personalized treatment approach with clinical translation potential, providing new ideas for enhancing the therapeutic effect against solid tumors such as TNBC. This article is protected by copyright. All rights reserved.