A novel naringenin-loaded plant protein nanocomplex accelerates corneal epithelial wound healing by remodeling the immune microenvironment.

This study explores the feasibility of pea protein isolate (PPI) as a topical ocular carrier to deliver naringenin (NAR), and develops an aqueous, solvent-free plant protein-polyphenol nanocomplex (PPI-NAR) for corneal epithelial repair. Molecular dynamics simulations suggested that the complex was stabilized by hydrophobic interactions and hydrogen bonding. PPI-NAR displayed substantially enhanced solubility (∼150-fold in water) and excellent ocular safety. Importantly, treatment accelerated wound closure by ∼1.7-fold, promoted nerve regeneration, and restored corneal sensitivity in a mouse model. Mechanistically, PPI-NAR modified the immune microenvironment by polarizing macrophages toward the M2 phenotype and suppressed IL-6 and TNF-α via modulation of HMGB1 and Sonic Hedgehog signaling, while elevating IL-10. These findings suggest that PPI-NAR offers a promising therapy with both anti-inflammatory and regenerative potential for corneal repair.