Hyaluronic Acid-functionalized Hesperidin-loaded Solid Lipid Nanoparticles for Mitigating Oxidative Stress: A Potential Strategy for Radiation-induced Skin Injury

Radiation-induced skin injury is a common, dose-limiting toxicity of cancer radiotherapy caused by excessive reactive oxygen species (ROS), inflammation, and impaired epidermal repair. Current topical treatments mainly offer symptomatic relief and do not effectively address intracellular oxidative stress. This study reports a hyaluronic acid–functionalized, hesperidin-loaded solid lipid nanoparticle (HSP-HA-SLN) system designed to enhance dermal delivery, skin retention, and intracellular antioxidant activity. HSP-HA-SLNs were prepared by solvent injection and optimized using a Central Composite Design to achieve sub-300 nm particle size and high entrapment efficiency, followed by hyaluronic acid surface functionalization. The optimized formulation was characterized by dynamic light scattering, electron microscopy, thermal, and crystallographic analyses. In vitro drug release, cytocompatibility, intracellular antioxidant activity, and ex vivo skin permeation and retention were evaluated. The nanoparticles exhibited sustained diffusion-controlled drug release, high cytocompatibility, and significantly improved intracellular ROS scavenging compared to free hesperidin. The observed intracellular ROS reduction supports the potential of this system in radiation-induced oxidative stress conditions. Ex vivo studies showed enhanced dermal deposition with minimal surface residue, indicating localized drug reservoir formation. Overall, the HSP-HA-SLN platform overcomes key solubility, permeability, and retention limitations of hesperidin and represents a promising topical nanotherapeutic approach for potential application in radiation-induced skin injury.