A Supramolecular Deferoxamine-Crisaborole Nanoparticle Targets Ferroptosis, Inflammation, and Oxidative Stress in the Treatment of Retinal Ischemia/Reperfusion Injury.

Abstract

Retinal ischemia-reperfusion (IR) injury is a major cause of vision loss worldwide, with ferroptosis, oxidative stress, and inflammation playing key roles in its pathogenesis. Currently, treatments targeting multiple aspects of this condition are limited. This study introduces a supramolecular nanoparticle combining the phosphodiesterase 4 (PDE4) inhibitor crisaborole and the ferroptosis inhibitor deferoxamine to address these pathological processes. Crisaborole forms a dynamic bond with deferoxamine via benzoxaborole-catechol chemistry, creating an amphiphilic molecule that assembles into nanoparticles. Treatment with these nanoparticles enhances glutathione peroxidase 4 (GPX4) levels, downregulates ferroptosis-related genes [Acyl-CoA synthetase long chain family member 4 (<i>Acsl4</i>), heme oxygenase 1 (<i>Hmox1</i>)], reduces inflammatory markers (interleukin-1 beta, interleukin-6, tumor necrosis factor alpha), and decreases reactive oxygen species. Electroretinogram and histochemical analysis confirm the nanoparticles' superior protective effects compared to control treatments. This study proposes a novel nanoparticle approach for retinal IR injury by simultaneously targeting multiple pathogenic pathways.