Click-crosslinked arginine-based nanoplatform for co-delivery of camptothecin and siSTAT3 for metastatic breast cancer therapy.

Metastatic breast cancer remains a major therapeutic challenge due to the limited efficacy of current treatments against both primary tumors and distant metastases. Here, we developed an arginine-based click-crosslinked nanoplatform for the co-delivery of camptothecin (CPT) and STAT3 siRNA (siSTAT3). The nanoplatform was constructed using a dibenzocyclooctyne-functionalized arginine derivative, where guanidinium-phosphate interactions enabled efficient siRNA loading and copper-free click crosslinking improved structural stability. Hyaluronic acid modification further enhanced tumor cell uptake through CD44 recognition. HDCPT@siSTAT3 achieved efficient intracellular delivery, lysosomal escape, and intracellular release of CPT and siSTAT3. In 4T1 breast cancer cells, HDCPT@siSTAT3 reduced STAT3 expression by approximately 50%, promoted apoptosis, and inhibited migration. In 4T1 breast tumor models, HDCPT@siSTAT3 suppressed tumor growth with minimal systemic toxicity. Moreover, the treatment significantly decreased lung metastatic burden in a 4T1-Luc metastasis model. The integration of arginine-based interactions, covalent cross-linking, and active targeting may provide a useful strategy for combined chemo-gene therapy in metastatic breast cancer.