A brain-targeted and ROS-responsive natural polysaccharide nanogel for enhancing antidepressant therapy

Abstract

Major depressive disorders are among the most common mental illnesses, and seriously affect the physical and mental health of patients. Emerging evidence indicates that the blood–brain barrier (BBB) and reactive oxygen species (ROS) microenvironment are major impediments to treating depression therapy, preventing drugs from exerting antidepressant effects. Herein, a transferrin/disulfide-modified natural polysaccharide nanogel was designed to cross the BBB and control the release of antidepressants in the brain, thereby enhancing antidepressant effects. The nanogels was dispersed in a thermoresponsive hydrogel, which enhanced mucoadhesiveness and reduced drug loss in the nasal cavity. In vitro and in vivo results demonstrated that the nanogels was highly efficient at crossing the BBB and had good biocompatibility, effectively delivering glycyrrhizic acid and paeoniflorin, two traditional Chinese medicine ingredients, to the brain and attaining ROS-response drug release. The nose-to-brain route increased the concentration of antidepressants in the brain, reduced the dosage, and enhanced antidepressant effects. The nanogel quickly reduced the immobility time of stress-exposed mice, alleviated depressive-like behaviors in chronic unpredictable mild stress rats, and improved antidepressant effects by regulating the ROS-induced mitogen-activated protein kinase and NOD-like receptor protein 3 signaling pathways. In summary, we designed a brain-targeted and ROS-responsive natural polysaccharide nanogel to enhance the effects of antidepressants, providing a promising new depression therapy strategy.