Biomimetic co-delivery nanoplatform overcomes CAF- and TAM-induced immunosuppression to augment therapeutic efficacy against triple-negative breast cancer.

Immune checkpoint blockade (ICB) has emerged as a cornerstone therapy for triple-negative breast cancer (TNBC); however, its clinical efficacy remains suboptimal due to the immunosuppressive tumor microenvironment (TME). TNBC is characterized by persistent activation of cancer-associated fibroblasts (CAFs) and infiltration of immunosuppressive cells, particularly tumor-associated macrophages (TAMs). Notably, the Hedgehog (Hh) signaling pathway plays a crucial role in both CAF activation and TAM polarization. To address these limitations, we developed an erythrocyte membrane-camouflaged biomimetic co-delivery nanoplatform encapsulating Vismodegib and BMS-1 (designated as E-V/B@NM). In vitro and in vivo studies demonstrated that the fabricated E-V/B@NM significantly accumulated in tumors and controllably released drugs in response to the acidic TME. The therapeutic agents effectively inhibited Hh pathway activation, which consequently suppressed the secretion of extracellular matrix (ECM) components by CAFs, and repolarized M2-like TAMs toward immunostimulatory M1 phenotype. Synergizing with PD-1/PD-L1 inhibition, this strategy significantly enhanced dendritic cells (DCs) maturation and antigen-presenting function, boosted CD8+ T cell infiltration and immune response, and effectively suppressed primary tumor progression and metastasis in TNBC murine models. Our findings highlight that the biomimetic nanoplatform based on E-V/B@NM remodels the TME by reprogramming both CAFs and TAMs, thereby overcoming immunosuppression and improving ICB efficacy in TNBC.