cCLT1-decorated nanodisk as a novel cancer-associated fibroblast-targeted curcumin delivery system for enhanced breast tumor metastasis treatment by TME remodeling

Breast cancer remains one of the leading causes of cancer-related mortality in women, with metastasis being the primary driver of treatment failure and poor prognosis. Multiple components within the tumor microenvironment (TME) work together to promote tumor metastasis, among which cancer-associated fibroblasts (CAFs) function as the central mediators of tumor-stroma crosstalk. In this study, we fabricated a novel nanodisk-based platform for curcumin (CUR) delivery to selectively suppress CAF activation. By functionalizing nanodisks (NDs) with the cyclic peptide CGLIIQKNEC (cCLT1), the resulting formulation (ND/P-CUR) enabled preferential CUR delivery to CAFs. Benefiting from both the structural advantages of NDs and the specific affinity of cCLT1 toward cellular fibronectin (cFN), ND/P-CUR effectively promoted CAF reprogramming and TME remodeling. Mechanistic investigations revealed that ND/P-CUR markedly reduced extracellular matrix (ECM) deposition, downregulated transforming growth factor-beta 1 (TGF-β1) expression, and suppressed tumor angiogenesis, thereby enhancing the inhibition of tumor growth and metastatic progression. Collectively, this CAF-targeted TME remodeling strategy based on cCLT1-functionalized NDs represents a promising therapeutic approach for breast cancer, and is expected to be applicable to the treatment of other stroma-rich tumors.