The programmed site-specific delivery of LY3200882 and PD-L1 siRNA boosts immunotherapy for triple-negative breast cancer by remodeling tumor microenvironment.

Despite the remarkable success of immunotherapies over the past decade, their effectiveness against triple-negative breast cancer (TNBC) is limited to a small subset of patients, mainly due to the low immunogenicity and unfavorable tumor microenvironment. In this study, we successfully constructed a programmed site-specific delivery nanosystem for the combined delivery of transforming growth factor beta (TGF-β) receptor inhibitor LY3200882 (LY) and PD-L1 siRNA (siPD-L1) to boost anti-tumor immunotherapy. As expected, LY in the outer layer of the nanosystem was released by stimulation of MMP2, and dramatically down-regulated the expression of extracellular matrix (ECM) in the tumor-associated fibroblasts (TAFs), and thus promoted the infiltration of effector T cells and penetration of nanomedicines. Simultaneously, the blockade of TGF-β by LY also triggered immunogenic cell death (ICD) of tumor cells and induced the maturation of dendritic cells. Moreover, the programmed design provided the siPD-L1/protamine cationic inner core with easier access to tumor cells and TAFs after MMP2-stimulated breakup of the outer layer, down-regulating the expression of PD-L1 in both types of cells. Notably, the synergistic effect of LY and siPD-L1 remarkably enhanced the tumor antigen presentation and immunosuppressive microenvironment remodeling, thus efficiently inhibiting the TNBC growth, metastasis, and recurrence. Therefore, the programmed site-specific delivery nanosystem is a promising drug delivery platform for boosting anti-tumor immunotherapy efficacy for TNBC.