ROS-responsive nanogels for brain targeted delivery of icariin in the treatment of Parkinson’s disease

Excessive reactive oxygen species (ROS)-induced nigrostriatal dopaminergic neuron degeneration is a cardinal pathological feature of Parkinson’s disease (PD). Although icariin, a natural antioxidant capable of scavenging ROS, shows therapeutic potential, it remains underutilized in clinical settings. This translational gap primarily stems from two pharmacological limitations: (1) inadequate blood–brain barrier (BBB) penetration that prevents effective delivery of icariin to the brain, and (2) the lack of targeted drug release at pathological sites, thereby diminishing its local neuroprotective efficacy against ROS-mediated neurodegeneration. To overcome these challenges, we developed a ROS-responsive selenocysteamine-alginate nanogel (ASeNG-ICA) that bypasses the BBB via nose-to-brain delivery and enables pathology-triggered drug release through diselenide bond cleavage in the high-ROS microenvironments characteristic of PD. In vitro studies demonstrated that the nanogels undergo ROS-responsive disintegration, resulting in sustained icariin release under oxidative conditions. Following intranasal administration in mice, ASeNG-ICA achieved rapid brain biodistribution. In a PD mouse model, this delivery system significantly reduced striatal malondialdehyde (MDA) levels, regulated antioxidant enzymes (HO-1, SOD) expression, alleviated oxidative stress and improved behavioral disorders, surpassing conventional free icariin therapy. Overall, ASeNG-ICA resolves critical delivery barriers in PD therapy, offering a new paradigm for neurodegenerative disease treatment.