Melanocortin 1 receptor-targeted peptide-functionalized liposomes for enhanced melanocyte-preferential drug delivery and anti-melanogenic efficacy.

Melanocyte-preferential drug delivery remains challenging due to limited targeting strategies for pigmentary disorders. Here, melanocortin 1 receptor (MC1R)-targeted liposomes (MELA-lipos) functionalized with melanotropic peptides are developed for melanocyte-directed delivery. Peptide-lipid conjugation is confirmed through multidimensional NMR spectroscopy and MALDI-TOF mass spectrometry. γ-MSH-conjugated MELA-lipo (MELA-lipoγ-MSH) shows threefold enhanced cellular uptake in B16F10 melanoma cells compared to bare liposomes, with internalization occurring through lipid raft-dependent endocytosis and macropinocytosis. Tri-culture experiments demonstrate melanocyte-preferential uptake over keratinocytes and fibroblasts. α-Arbutin-loaded MELA-lipoγ-MSH achieves 52.3% melanin inhibition and sustained tyrosinase suppression (25.4% at 72 h) in cell culture. In reconstructed human skin models, MELA-lipoγ-MSH results in melanin reduction and decreased tyrosinase expression. These findings indicate that MC1R-targeted liposomal delivery achieves melanocyte-preferential internalization and anti-melanogenic efficacy, suggesting translational potential in the topical management of pigmentary disorders and cosmetic depigmentation applications.