Lipid Nanoparticle-Mediated Targeted Delivery of MEGF10 siRNA to Astrocytes Reduced Synaptic Phagocytosis and Promoted Stroke Recovery in Mice

Astrocyte-mediated synaptic phagocytosis plays a critical role in regulating brain development and disease progression. Our previous studies have demonstrated that MEGF10, a key molecule mediating astrocytic phagocytosis of synapses, is remarkably upregulated during the chronic phase of stroke, leading to synapse loss and exacerbating brain injury. Targeting MEGF10 to reduce synapse engulfment has emerged as a promising therapeutic strategy for stroke. However, achieving precise astrocyte-targeted modulation remains a significant challenge, primarily due to the absence of efficient and specific gene delivery systems. Lipid nanoparticles (LNP) functionalized with peptides or antibodies are promising gene delivery vectors for treating central nervous system (CNS) diseases. Herein, we developed an LNP system loaded with MEGF10 siRNA and functionalized with an astrocyte-targeting peptide AS1 (siMEGF10-LNP@AS1). Ex vivo imaging and immunostaining results showed that injection of siMEGF10-LNP@AS1 efficiently delivered MEGF10 siRNA to astrocytes, downregulated MEGF10 expression in stroke mice, and reduced astrocytic phagocytosis of synapses. This intervention enhanced synaptic density while maintaining good biocompatibility. Furthermore, administration of siMEGF10-LNP@AS1 improved motor and cognitive function and reduced brain atrophy volume in stroke mice. Overall, our study establishes a robust platform for astrocyte-targeted gene modulation, offering a potential therapeutic strategy for CNS diseases.