Self-assembling chemically modified siRNA nanorings for RNAi therapy and neuroprotection in Alzheimer’s disease

The development of RNA interference (RNAi) therapy offers a potential solution for Alzheimer’s disease (AD). However, the brain-blood barrier (BBB) with its selective permeability and pharmacokinetic-related challenges poses restrictions on the delivery of small interfering RNA (siRNA) to the central nervous system (CNS). In this study, we demonstrate that the incorporation of 2′-fluoro (2′-F) substitutions and L-carnitine modification facilitates the self-assembly of siRNA through triple interaction, leading to the formation of nanorings, called LCSF-NR. Based on the enhanced cellular uptake and lysosomal escape by 2′-F substitution and the transport across the BBB promoted by L-carnitine, the nanorings realized the improved brain-targeted delivery of siRNA, both in zebrafish and mice models. Moreover, our findings highlight the therapeutic potential of LCSF-NR formulation in an AD zebrafish model through a synergistic effect of downregulating the β-site APP cleavage enzyme 1 (BACE1) gene and L-carnitine-mediated neuroprotection, effectively inhibiting pathological processes. Overall, these results suggest that the chemical modification-based siRNA self-assembly strategy enables trans-BBB delivery and presents a concise approach for synergistic therapy of AD.