Paeonol-Loaded Cyclodextrin/Composite Hydrogel for Enhanced Transdermal Delivery and Skin Photoaging Repair

Skin photoaging is closely associated with oxidative stress, inflammatory responses, and dysregulated collagen metabolism. Paeonol (Pae) possesses antioxidant and anti-inflammatory activities; however, its poor water solubility and short skin retention time limit its topical application. In this study, a transdermal delivery system based on a carboxymethyl chitosan (CMCS)/Carbomer 940 (Carb940) composite gel loaded with hydroxypropyl-β-cyclodextrin inclusion complexes of paeonol (Pae-CD) was developed. Pae-CD was prepared using an ultrasound-assisted saturated aqueous solution method, and the physicochemical properties, sustained-release behavior, transdermal permeation, antioxidant activity, and safety of Pae-CD/gel were evaluated. Furthermore, a mouse model of skin photoaging induced by combined ultraviolet A (UVA)/ultraviolet B (UVB) irradiation was established to investigate its reparative effects in vivo. The results showed that Pae-CD/gel exhibited a homogeneous three-dimensional porous structure, favorable sustained-release characteristics, enhanced skin retention capacity, and good cellular compatibility. In vivo experiments demonstrated that Pae-CD/gel markedly ameliorated ultraviolet-induced skin dryness, abnormal epidermal thickening, and dermal collagen loss. It also reduced oxidative stress and inflammatory factor levels, down-regulated matrix metalloproteinase-1 (MMP-1) and matrix metalloproteinase-3 (MMP-3) expression, and promoted the restoration of collagen type I (COL-1) and hydroxyproline (HYP) levels. Systemic safety evaluation revealed no obvious toxicity. In summary, Pae-CD/gel exerts antioxidant and anti-inflammatory effects and regulates collagen metabolism by enhancing transdermal delivery and local retention, thereby providing a safe and effective topical delivery strategy for the repair of skin photoaging.