Microglial‐Biomimetic Memantine‐Loaded Polydopamine Nanomedicines for Alleviating Depression

Abstract Depression is a common psychiatric disorder, and monoamine‐based antidepressants as first‐line therapy remain ineffective in some patients. The synergistic modulation of neuroinflammation and neuroplasticity could be a major strategy for treating depression. In this study, an inflammation‐targeted microglial biomimetic system, PDA‐Mem@M, is reported for treating depression. Microglial membrane‐coated nanoparticles penetrate the blood‐brain barrier and facilitate microglial targeting. Subsequently, owing to the excellent free radical‐scavenging capacity, PDA‐Mem@M attenuate the brain inflammatory microenvironment. After on‐demand release from the nanoparticles, memantine increases the expression of brain‐derived neurotrophic factors and reverses the loss of synaptic dendritic spines. Further, in vivo studies demonstrate that PDA‐Mem@M effectively alleviate depression‐like behaviors to a greater extent than memantine or polydopamine nanoparticles (PDA) monotherapy. This synergistic strategy, with satisfactory biosafety and strong anti‐inflammatory and synaptic plasticity restoration effects, is conducive to advances in depression therapy.