A multifunctional mitochondria-targeted nanoparticle for the effective treatment of dry eye disease via reactive oxygen species scavenging

Dry eye disease is a prevalent ocular surface disorder primarily driven by oxidative stress and inflammation, remains a therapeutic challenge due to the limitations of current treatments. In this study, we developed a multifunctional nanoparticle system, using a layer-by-layer self-assembly strategy to enhance the delivery and efficacy of a natural antioxidant, proanthocyanidin (PC). The nanocomplex consists of a caseinate-proanthocyanidin core, further modified with chitosan-triphenylphosphonium (CS-TPP) for mitochondrial targeting and coated with hyaluronic acid (HA) to prolong ocular surface retention. In vitro and in vivo studies demonstrated that PC-Casein/CS-TPP/HA (CCH@PC) effectively scavenges reactive oxygen species with an elimination efficiency of up to 70 %, protects mitochondrial function, and significantly extends corneal residence time compared to conventional eye drops. Moreover, in a murine model of dry eye, CCH@PC markedly alleviated clinical symptoms, effectively promotes the tear secretion of the dry eye model mice, increasing from 2.20 mm to 5.06 mm, suppressed inflammatory responses, and promoted corneal epithelial repair. These findings highlight the potential of CCH@PC as a targeted, sustained, and multifunctional nanotherapeutic platform for treating dry eye disease and other oxidative stress-related ocular pathologies. • A multifunctional nanoparticle CCH@PC was developed for dry eye therapy. • CCH@PC enables mitochondrial targeting and prolonged ocular retention. • It effectively scavenges ROS and alleviates inflammation in vitro and in vivo. • CCH@PC restores corneal integrity and tear secretion in a dry eye model.