Lipid-conjugated siRNA targeting SARM1 enables CNS silencing and mitigates alzheimer-like phenotypes.

RNA interference (RNAi) therapeutics have achieved clinical success in liver disease, but their application to central nervous system (CNS) disorders remains limited. Here, we developed a lipid-conjugated siRNA to silence sterile alpha and TIR motif-containing protein 1 (SARM1), a key executor of axon degeneration associated with neuroinflammatory injury, and evaluated it in an Alzheimer-like model. siRNAs targeting conserved regions of human SARM1 and mouse Sarm1 were designed and screened in neural cells, and C16 lipid conjugation together with a 5'-(E)-vinylphosphonate (5'-VP) modification was used to support in vivo delivery. In mice, intracisterna magna (ICM) administration reduced Sarm1 mRNA in the hippocampus at the two-week time point. In the intracerebroventricular streptozotocin (STZ-ICV) model, two ICM doses of VD07C attenuated hyperlocomotion and partially improved selected spatial-memory-related endpoints. VD07C also reduced hippocampal SARM1 protein and cADPR, increased NAD+, and was associated with lower p-Tau, glial activation markers, and NF-κB/TNF-α expression. These findings provide convergent evidence of molecular and functional target engagement and support further evaluation of lipid-conjugated SARM1 siRNAs in progressive neurodegeneration models.