Geographic variation in ginger-derived nanovesicle lipids identifies chiral protein recognition as a determinant of...

Plant-derived exosome-like nanovesicles (PELNs) represent natural nanocarriers for advanced nutrient delivery, with their lipid being a underutilized resource. However, a question is whether geographical variation of plant alters the lipid composition of PELNs to impact immune cells. To investigate this, geographical variation in ginger-derived exosome-like nanoparticles (GELNs) was leveraged as a natural lipid library. The first step was to determine whether geographical variation triggered biosynthetic divergence in GELNs lipids. Our approach combined lipidomic profiling, functional assays, and computational simulations to identify lipids that govern B-cell internalization and to elucidate their underlying mechanisms. Among 1202 lipids, 88 were differentially abundant (VIP >1.2, p < 0.05), and 36 correlated with internalization (|ρ| > 0.65, p < 0.05). Molecular docking showed DG (32:2) binding strongly to fatty acid amide hydrolase (FAAH) (-8.00 ± 0.17 kcal/mol) and PG (23:2) variants preferring autotaxin (ATX) (-6.97 to -7.43 kcal/mol), with both exceeding their affinity for bovine serum albumin, indicating a protein corona-independent mechanism. Molecular dynamics simulations validated the specificity predicted by docking, confirming that DG (32:2) and PG (23:2) form more stable complexes with FAAH and ATX, respectively. These data demonstrated a structure-activity relationship in which the promotion and inhibition of B-cell internalization are mediated by the key lipids DG (32:2) and PG (23:2) engaging FAAH and ATX through stereospecific interactions, respectively. This work establishes a phenotype-driven pipeline that bridges botanical diversity with precision nutrition, providing a source of functional dietary lipids, a mechanistic basis for their immunomodulatory effects, and a robust tool for quality evaluation.