Polyphenol-Mediated Engineering of Lipid Nanoparticles With Crystalline Mesophases

Lipids self-assemble into lipid nanoparticles (LNPs) with different crystalline mesophases, including lamellar and nonlamellar (e.g., cubic and hexagonal) mesophases. Although various additives can modulate lipid curvature, the formation of nonlamellar crystalline mesophases in LNPs typically depends on specific phase-forming lipids, which limits the overall design space and structural versatility for cargo loading. Herein, a new class of nonlamellar LNPs is engineered through the one-step assembly of two components-a polyphenol and a lipid-where the lipid mesophases are modulated by the polyphenols in a concentration-dependent manner. The polyphenol-based LNPs exhibit ordered Im3m micellar cubic or hexagonal nanostructures and can load metal ions, small-molecule drugs, polypeptides, proteins, polysaccharides, and mRNA. The present study establishes an approach to generate nonlamellar LNPs with ordered nanostructures and functional cargos for diverse applications.