Simple construction of starch-lipid-protein complexes for enhancing the encapsulation and delivery performance of mesalazine-loaded Pickering emulsions.

Pickering emulsions are attractive for oral drug delivery owing to their stability, multifunctionality, and environmental compatibility. However, designing stabilizers capable of efficiently encapsulating hydrophilic drugs remains challenging. Herein, a cassava starch-palmitate-zein complex (CPZc) with three-dimensional sponge-like and type VII crystalline structures was fabricated via a simple mechanical activation (MA) process. MA promoted the embedding of palmitate into starch helices, while partially unfolded zein crosslinked onto the starch-lipid surface via hydrogen bonding and electrostatic interactions, forming a reticular shell. When used as an emulsifier, CPZc stabilized mesalazine-loaded Pickering emulsions with excellent storage stability (EI= 91.8% and D₃,₂= 17.1 μm) and high drug retention (92.4% after 28 d). Notably, 72.9% of mesalazine remained after simulated gastric digestion. The multiscale network of CPZc enabled dual drug-loading mechanisms: hydrogen bonding between protein polar groups and mesalazine and physical entrapment within hydrophilic lamellae. This work provides a facile and sustainable approach to construct the starch-lipid-protein ternary complexes and demonstrates their potential as efficient carriers for the gastrointestinal-targeted delivery of hydrophilic drugs.