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.　©　Science　China　Press　2025.