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

A chondroitin sulfate-functionalized GSH-responsive lipid-nanoparticle (CSD@DNLP) was developed for co-delivering doxorubicin (DOX) and nifuroxazide (NIF) in metastatic melanoma treatment. • Chondroitin sulfate-functionalization improved cellular uptake through targeting CD44-receptors and enhanced drugs release in tumor-mimic environment. • Synergistic effects were observed in tumor growth inhibition and metastasis repression through NIF-mediated STAT3 phosphorylation blockade and DOX-induced DNA damage. • CSD@DNLP demonstrated a promising strategy in metastatic melanoma. Tumor metastasis results in high mortality rate in patients with advanced melanoma. The hyperphosphorylation of signal transducer and activator of   transcription   3 (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. Download: Download high-res image (162KB) Download: Download full-size image