Supramolecular protein-peptide co-assembly mediated by Ca2+ enhances curcumin penetration through intestinal barriers

The size-tunable protein-peptide co-assembly strategy has provided novel insights into the design of high-bioavailability delivery vehicles. This study involved a calcium ion (Ca²⁺)-mediated co-assembly (CA) of casein (CN) and egg white peptide (EWP) to encapsulate the model hydrophobic curcumin (Cur), denoted as EWP-Ca²⁺-CN-Cur. The findings reveal that Ca²⁺ acts as a pivotal orchestrator in modulating the microscopic interaction patterns of co-assembly, inducing non-covalent interaction reconstruction through entropy-enthalpy co-mediated effects to drive assembly processes while triggering intra-assembly cross-β sheets compaction. The resulting ultrasmall nanospheres (63 ± 0.40 nm) achieved concurrent optimization of guest molecule encapsulation capacity and stability enhancement. More importantly, EWP-Ca²⁺-CN-Cur exhibits remarkable enhancement in Cur internalization in Caco-2 cells, alongside excellent mucus penetration, epithelial absorption, and transport efficiency. It also demonstrates intestinal sustained-release properties and potential anti-inflammatory effects. We anticipate that this Ca²⁺-mediated protein-peptide co-assembly strategy could provide a facile approach for the design of biocompatible oral delivery systems and the enhancement of bioavailability for hydrophobic components.