Injectable Hyaluronic Acid Hydrogel Integrated with Hybrid Nanovesicles for Synergistic Enhancement of Transdermal Drug Delivery

Plant-derived nanovesicles offer promising potential for transdermal drug delivery due to their inherent biocompatibility and low immunogenicity, yet face limitations in drug loading, structural stability, and functional optimization. This study presents a versatile Hybrid-Gel platform that integrates CoQ10-loaded hybrid vesicles with an injectable, pH-responsive hydrogel to enhance localized drug delivery. High-purity nanovesicles are isolated using an optimized ultracentrifugation (UC) and size-exclusion chromatography (SEC) method, then hybridized with liposomes to improve encapsulation and skin penetration. To further optimize localized delivery performance, an injectable binary hydrogel system is then introduced. This hydrogel, formed via Schiff base crosslinking between hyperbranched polyethylene glycol and aldehyde-modified hyaluronic acid (A-HA), exhibits mild gelation conditions, excellent injectability, and strong tissue adhesion. The hydrogel effectively encapsulates hybrid nanovesicles, ensuring enhanced stability, ease of administration, and controlled, pH-responsive release. As a proof of concept, an in vitro permeation test with porcine skin model demonstrates that the hydrogel significantly improves CoQ10 penetration, achieving a more than fourfold increase in transdermal efficiency compared to free CoQ10, suggesting superior bioavailability. This synergistic approach, combining hybrid nanovesicle-mediated drug transport with a dynamic hydrogel matrix, offers a robust and versatile platform for localized transdermal therapy, with potential applications in precision medicine, regenerative treatments, and chronic disease management.