Chondroitin sulfate-functionalized GSH-responsive lipid-nanoparticle inhibits melanoma metastasis through suppressing STAT3 activation.

Tumor metastasis results in high mortality rate in patients with advanced melanoma. The hyperphosphorylation of signal transducer and activator oftranscription3 (STAT3) is closely associated with the proliferation and metastasis of melanoma. Here, we proposed a lipid-nanoparticle (CSD@DNLP) derived from the chondroitin sulfate (CS)-conjugated deoxycholic acid (DOCA) polymer (CS-ss-DOCA, CSD) for the co-delivery of doxorubicin (DOX) and STAT3 inhibitor nifuroxazide (NIF) in metastatic melanoma treatment. The superior affinity between CS and overexpressed CD44 receptors in B16F10 cells resulted in 3.3-fold enhancement of cellular uptake compared to free DOX. CSD@DNLP maintained structural stability in physiological conditions, while achieving 75.15% cumulative release within 48 h under a tumor-mimic concentration of glutathione (GSH, 20 mM). Synergistic effects were observed through NIF-mediated STAT3 phosphorylation blockade and DOX-induced DNA damage, resulting in 3.2-fold enhancement in apoptotic cells versus free drugs. In lung metastasis mice, CSD@DNLP suppressed metastatic nodule formation (36% of free DOX + NIF) via dual downregulation of matrix metalloproteinases-2 (MMP-2) and metalloproteinases-2 (MMP-9). This CS-functionalized GSH-responsive lipid-nanoparticle demonstrates a promising strategy in metastatic melanoma.