A Nanoliposome Platform Co-Delivery of Hydroxypinacolone Retinoate and Carnosine for Enhanced Epidermal/Dermal Delivery and Multi-Functional Anti-Aging Efficacy

Background: Effective anti-aging requires dual strategies to stimulate regeneration and counteract damage. While the combination of hydroxypinacolone retinoate (HPR) and carnosine (CA) holds great promise, their effectiveness is hampered by instability and poor skin penetration. Methods: To overcome these challenges, this study developed HPR and CA co-encapsulated nanoliposomes (HC-NLPs) via high-pressure homogenization as an advanced epidermal/dermal delivery system. Results: HC-NLPs markedly improved skin retention of HPR (58.97%) and CA (111.36%) compared to the free combination (Free-HC). In cellular studies, HC-NLPs displayed excellent biocompatibility and demonstrated a 4.7-fold higher cellular uptake. This led to enhanced proliferative (EdU positive rate increased by 78.32%) and migratory (wound closure improved by 31.5%) capacities. Moreover, HC-NLPs effectively reinforced multiple skin-protective processes associated with aging, including enhanced resistance to oxidative and glycation-induced damage, suppressed inflammatory responses, and strengthened cellular barrier integrity. In 3D skin models, HC-NLPs promoted collagen deposition and improved tissue morphology compared to Free-HC. Their superior in vivo antioxidant and anti-aging effects were further validated in Zebrafish assays. HC-NLPs effectively co-deliver HPR and CA, markedly improving their stability, skin penetration, and cellular internalization. Conclusions: The formulation demonstrates comprehensive pro-regenerative, anti-inflammatory, antioxidative, and anti-glycation effects, representing a promising nano-delivery strategy for advanced anti-aging skincare.