Dendrimer Nanogels with Built-in Free Radical Scavenging Enable Efficient Topical Delivery of a Hydrophilic Antioxidant to Restore Lens Redox Balance for Cataract Treatment

Cataract is a leading cause of vision impairment worldwide and are primarily caused by oxidative stress that damages and aggregates lens proteins, leading to lens opacification. However, the eye's anatomical barriers limit the penetration and bioavailability of antioxidant therapies. To address this challenge, a dendrimer-based nanogel with a built-in reactive oxygen species (ROS)-scavenging capability developed by us was employed to deliver the antioxidant N-acetylcysteine (NAC) to the lens. NAC was loaded into a generation-5 PEGylated poly(amidoamine) dendrimer (G5-PEG-TK, termed the GPT) nanogel. The resulting NAC-GPT was characterized for its ROS-scavenging activity, bioavailability, and corneal permeability. The efficacy of NAC-GPT was evaluated <i>ex vivo</i> and <i>in vivo</i> using a sodium selenite (Na₂SeO₃)-induced cataract model. Both <i>ex vivo</i> and <i>in vivo</i> results demonstrated that NAC-GPT significantly increased the level of NAC accumulation in the lens. Furthermore, the <i>in vivo</i> study shows that NAC-GPT significantly increased the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), an indicator of redox balance restoration. In particular, the GSH/GSSG ratio in NAC-GPT-treated lenses was nearly 2-fold higher than that of the untreated cataract control. These findings indicate that the GPT nanogel platform can effectively deliver antioxidants to the eye and is a promising noninvasive antioxidant delivery strategy with the ability to restore redox balance in cataract.