A multipronged strategy for encephalitis: Oxidative stress reduction and inflammatory microenvironment modulation by a neuroprotective selenium-based nanomedicine

The elevated levels of reactive oxygen species (ROS) in the inflammatory microenvironment associated with encephalitis, trigger neurological damage and immune imbalance. Owing to the complex environment of the brain, there are few effective therapies for the treatment of encephalitis. Accordingly, the development of multifunctional drugs to alleviate encephalitis under this complex microenvironment is urgently needed. In this study, multifunctional metal-polyphenol-coated selenium nanoparticles (BSe@MT) were synthesized by combining albumin-dispersed selenium nanoparticles (BSe) and a metal-polyphenol complex based on manganese ions and tannic acid. BSe@MT exhibited superoxide dismutase-like and glutathione peroxidase-like activities, which enabled scavenging of the excess intracellular ROS, thus effectively inhibiting neuronal apoptosis and alleviating microglia inflammatory responses in vitro. Furthermore, the nanoparticles exhibited good in vivo therapeutic effects in a mouse model of encephalitis by effectively decreasing the ROS levels, lipid peroxidation, and neuronal loss. In addition, BSe@MT modulated the inflammatory microenvironment associated with encephalitis by inhibiting microglia polarization and neutrophil infiltration, downregulating the levels of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α), and upregulating the levels of anti-inflammatory cytokines (IL-10). Further examination of the mechanism revealed that BSe@MT significantly downregulated the expression of inflammatory-response-related genes such as Map3k8, Socs3, and Cxcl10, thereby alleviating the inflammatory response. Moreover, BSe@MT displayed good biocompatibility and was primarily metabolized by the liver and kidneys. Overall, BSe@MT is expected to provide a safe, effective, and multipronged strategy for the treatment of encephalitis by rebalancing the complex microenvironment.