Regulating LipidDroplet Interface Based on MFGM to Promote the Humanization of InfantFormula

Abstract To examine whether interfacial milk fat globule membrane (MFGM) remodeling improves lipid digestion and metabolism, three infant formulas (IFs) were developed referencing human milk (HM): IF1 (no exogenous MFGM supplementation), IF2 (wet-mixed MFGM), IF3 (dry-blended MFGM). Interface analysis confirmed IF1 droplets were coated with whey and casein; MFGM assembled on IF2 to restructure interfacial proteins and phospholipids, while most MFGM stayed dispersed in IF3′s aqueous phase. In vitro digestion showed IF2 had HM-similar particle size and zeta potential trends, and its free fatty acid release was 58.34% higher than IF1 and 18.27% higher than IF3. Serum metabolomics found IF2’s metabolic profile matched HM most closely. In cognitive tests, IF2 exhibited shorter escape latency and higher hippocampal BDNF and NeuN expression than IF1. Overall, interfacial MFGM rearrangement promotes lipid digestion and metabolism with improved spatial memory. The present findings lay a theoretical foundation for infant formula optimization, requiring further clinical validation.