Background Developing innovative non-invasive formulations against skin photoaging is of considerable importance.

Objective To develop a novel chitosan-β-cyclodextrin/hyaluronic acid hybrid hydrogel (CS-β-CD-HAs) for the non-invasive and efficient delivery of HA, and evaluate its efficacy against skin photoaging in vivo.

Methods CS-β-CD-HAs were prepared and characterized using X-Ray diffraction, fourier transform infrared spectroscopy, scanning electron microscope, and rheology. Nine SD rats were randomly divided into blank control group, CS-β-CD-HAs group, and ultrapure water group to assess skin hydration capacity. Twenty SD rats were randomly divided into control group, photoaging model group, hydrogel topical application group (CS-β-CD-HAs), and HA injection group (INJ-HAs). A photoaging model was established on the dorsal skin of rats by incremental exposure to UVA and UVB irradiation. Therapeutic effects were evaluated through macroscopic observation and photoaging scoring, histopathology (HE and Sirius Red staining), gene expression (RT-qPCR analysis of Col-1, Col-3, Elastin, and Mmp-3 mRNA), and biochemical assays (Hyp content, SOD activity, and MDA content).

Results The successfully prepared CS-β-CD-HAs exhibited a stable three-dimensional porous network structure with good swelling capacity, self-healing properties, and excellent transdermal performance. Cell experiments showed that CS-β-CD-HAs significantly promoted the proliferation and migration of human skin fibroblasts, indicating good cytocompatibility. Animal experiments demonstrated that topical application of CS-β-CD-HAs significantly enhanced skin hydration capacity (P < 0.001). Compared with the Model group, CS-β-CD-HAs treatment improved the macroscopic photoaging score (P < 0.001), alleviated dermal collagen loss (P < 0.001), upregulated mRNA expression of Col-1, Col-3, and Elastin (P < 0.05), suppressed Mmp-3 mRNA expression (P < 0.01), increased Hyp content (P < 0.05), enhanced SOD activity (P < 0.05), and reduced MDA levels (P < 0.05). No statistically significant difference in anti-photoaging efficacy was observed between topical application of CS-β-CD-HAs and injection of the same molecular weight HA.

Conclusion CS-β-CD-HAs prove to be an efficient non-invasive HA delivery material, effectively ameliorating skin photoaging by maintaining extracellular matrix homeostasis and mitigating oxidative stress damage.