Engineering EVs‐Mediated mRNA Delivery Regulates Microglia Function and Alleviates Depressive‐Like Behaviors

Abstract The development of new non‐neurotransmitter drugs is an important supplement to the clinical treatment of major depressive disorder. The latest development of mRNA therapy provides the possibility for the treatment of some major diseases. The endoplasmic reticulum (ER) and mitochondria constitute a highly interconnected set of fundamental organelles within cells. The interconnection between them forms specific microdomains that play pivotal roles in calcium signaling, mitochondrial dynamics, inflammation, and autophagy. Perturbations in ER‐mitochondrial connections may contribute to the progression of neurological disorders and other diseases. Herein, an extracellular vesicles‐based delivery system, grounded in mRNA gene therapy and integrated with nanomedicine technology is devised. This system is engineered to traverse the blood–brain barrier and specifically target the central nervous system (CNS), facilitating the simultaneous delivery of mRNA drugs and metallic nanozymes into the brain. This dual‐pronged approach, targeting ER and mitochondrial crosstalk, inhibits microglial overactivation, promotes M2 polarization of microglia, and suppresses the NF‐κB signaling pathway. Consequently, it significantly alleviates Lipopolysaccharides‐induced neuroinflammatory responses and ameliorates anxiety‐ and depression‐like behaviors. This study demonstrates a novel antidepressant therapeutic strategy and establishes a new paradigm for mRNA gene therapy in CNS diseases.