Valorization of Paris polyphylla Byproducts: Integrated Multi-Omics and Molecular Docking Reveal the Anti-Melanogenic Mechanism of Plant-Derived Nanovesicles via the AKT/GSK3β/MITF Axis

Abstract

Valorizing agricultural byproducts into functional ingredients is highly desirable. Herein, plant-derived nanovesicles (PDNVs) from Paris polyphylla stems/leaves (SL-EXO) exhibited potent anti-melanogenic properties, whereas root-derived PDNVs were ineffective. In vitro, SL-EXO achieved 92.66% cell-free tyrosinase inhibition, while α-arbutin was 49.78%. In vivo, SL-EXO ameliorated the pigmentation-driving oxidative/senescent microenvironment in zebrafish and reduced macroscopic melanin by ~66%. Crucially, SL-EXO reversed α-MSH-induced hyperpigmentation in B16F10 cells while maintaining excellent biocompatibility up to 0.15 mg/mL, displaying a vastly superior safety margin compared to α-arbutin (which induced cytotoxicity at 0.075 mg/mL). To decode this, multi-omics profiling revealed that SL-EXO utilizes a chloroplast-derived biomimetic lipid architecture (enriched in MGDG/DGDG) to efficiently deliver potent flavonoid payloads. Molecular docking demonstrated exceptional predictive structural affinities (binding energies up to −10.9 kcal/mol) between these phytochemicals and AKT1. Finally, pharmacological rescue assays validated that SL-EXO arrests melanogenesis by targeting the AKT1 pathway, thereby downregulating the p-AKT/p-GSK3/MITF signaling cascade and silencing melanogenic genes. This study establishes a rigorous multi-omics paradigm for upcycling botanical wastes into exceptionally safe and efficacious natural anti-melanogenic nanotherapeutics.