MicroRNA-loaded antioxidant nanoplatforms for prevention and treatment of experimental acute and chronic uveitis

Abstract

Uveitis, a frequently recurrent inflammatory condition of the uvea, poses a significant risk of visual impairment and blindness, primarily due to the excessive generation of reactive oxygen species (ROS) and the activation of signaling pathways that propagate inflammatory responses. Despite the widespread use of corticosteroid eye drops as a standard treatment, these therapies are hindered by limited efficacy, adverse side effects, and poor ocular bioavailability. To address these challenges, polyethyleneimine (PEI)-modified polydopamine (PDA) carrying microRNA-132-3p (miR-132), namely PEI/PDA@miR-132, was developed to simultaneously neutralize ROS and attenuate inflammation in experimental models of acute and chronic uveitis. Mechanistically, PEI/PDA@miR-132 demonstrated remarkable efficacy by suppressing ROS production, inhibiting the pro-inflammatory polarization of macrophages, and downregulating the IκBα/nuclear factor-kappa B (NF-κB) p65 signaling pathway. These effects culminated in the reduction of pro-inflammatory cytokines and mitigation of apoptosis. Therapeutically, PEI/PDA@miR-132 provided significant relief from hallmark symptoms of uveitis, including iris congestion, inflammatory exudation, and retinal folds, while exhibiting superior retinal safety compared to commercially available dexamethasone. Furthermore, it showcased excellent biocompatibility, positioning it as a promising therapeutic strategy for managing oxidative stress- and inflammation-driven diseases such as acute and chronic uveitis.