Tumor microenvironment-responsive self-assembling nanotherapeutics integrating chemo-, anti-angiogenic, and immunostimulatory therapy for triple-negative breast cancer.

Triple-negative breast cancer (TNBC) remains a significant clinical challenge due to the lack of actionable targets, dose-limiting cardiotoxicity, and the limited efficacy of single-modality therapies. Doxorubicin (DOX), a first-line chemotherapeutic agent, is constrained by inadequate tumor targeting and systemic toxicity. In this study, we identified an SML peptide with high binding affinity for TNBC through in vitro and in vivo investigations. Fibroblast activation protein-alpha-α (FAP-α), which is highly expressed by cancer-associated fibroblasts (CAFs) within the TNBC tumor microenvironment (TME), was exploited as a tumor-specific trigger for targeted drug release. We developed a TME-responsive self-assembled peptide-based nanoplatform (QGS@DOX, DOX-loaded QGS self-assembled nanocarrier) that integrates g active tumor targeting, FAP-α-triggered cleavage, anti-angiogenic activity, and DOX chemotherapy. QGS@DOX demonstrated enhanced tumor accumulation, prolonged circulation time, and controlled drug release. In vivo, it effectively inhibited tumor growth and metastasis while reducing DOX-induced cardiotoxicity. Mechanistic studies revealed that QGS@DOX suppressed epithelial-mesenchymal transition (EMT), induced immunogenic cell death (ICD), and activated the cGAS-STING pathway, thereby remodeling the TME. Importantly, moesin (MSN) was identified as a novel target of the SML targeting peptide, uncovering a previously unrecognized mechanism for TNBC-specific delivery. To our knowledge, this is the first report of an integrated nanoplatform combining FAP-α responsiveness, SML-MSN targeting, anti-angiogenesis, chemotherapy, and cGAS-STING-mediated immunotherapy for TNBC. These findings present a promising strategy for precise, multimodal treatment of TNBC.