Construction of zein–silk fibroin–phospholipid hybrid vesicles for efficient transdermal co-delivery of hydrophilic and hydrophobic actives

Zein-SF-phospholipid hybrid vesicles with core–shell structure was formed. • Hybrid vesicles enabled co-delivery of natural hydrophobic/hydrophilic actives. • Hybrid vesicles significantly enhanced light and storage stability of bioactives. • Hybrid vesicles markedly enhanced transdermal delivery of actives. • Hybrid vesicles exhibited synergistic whitening in zebrafish with low toxicity. Combined use of hydrophilic and hydrophobic bioactives offers synergistic therapeutic and functional benefits; however, their distinct solubility characteristics hinder efficient co-encapsulation and synchronized delivery, highlighting the need for advanced co-delivery systems. Herein, a zein–silk fibroin–phospholipid hybrid vesicle (Z–SF–PC) was constructed for the concurrent co-encapsulation and efficient co-delivery of hydrophilic and hydrophobic bioactive compounds. In this compartmentalized system, hydrophobic zein was integrated into the phospholipid bilayer, while hydrophilic SF structured the aqueous core, creating spatially segregated domains favorable for dual loading. Using vitamin C (VC) and resveratrol (Res) as model bioactives, the effects of the zein-to-SF ratio on vesicle morphology, stability, and encapsulation performance were systematically investigated. At an optimal zein-to-SF ratio of 1:1, the hybrid vesicles exhibited densely packed molecular architecture, high colloidal stability, and superior encapsulation efficiencies (> 80% for both model compounds). The Z–SF–PC system also significantly improved the photostability of the encapsulated actives and demonstrated enhanced antioxidant and anti-melanogenic activities. In vitro transdermal studies revealed that the hybrid vesicles markedly enhanced skin permeation of VC and Res by 4.51-fold and 2.41-fold, respectively, compared to their free forms. In zebrafish models, the co-loaded vesicles exhibited potent whitening effects at bioactive doses lower than arbutin, while showing excellent biocompatibility (LC 50 = 1075.58 mg L −1 ). These findings underscore the central role of zein and silk fibroin as functional biological macromolecules in constructing a robust, multifunctional co-delivery hybrid vesicle for advanced dermatological and cosmetic applications. Download: Download high-res image (221KB) Download: Download full-size image