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Cardiovascular disease (CVD) is the leading cause of death globally and is exacerbated by elevated blood levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TGs). Existing approaches for decreasing blood lipid levels rely on daily medications, leading to poor patient adherence. Gene therapy represents a promising "one and done" strategy to durably reduce blood lipid levels. has emerged as a potential target for gene therapy, as naturally occurring loss-of-function variants are cardioprotective. Here, we use lipid nanoparticles to package and deliver CRISPR adenine base editors (ABEs), which enable gene knockout without requiring potentially harmful DNA double-strand breaks. We package ABE mRNA and a synthetic guide RNA targeted to disrupt an important splice site in , which we administered to mice intravenously. We achieved over 60% base editing in the liver and durable reductions in serum ANGPTL3, LDL-C, and TGs for at least 100 days. Notably, blood lipid levels remained low when mice were challenged with a high-fat high-cholesterol diet up to 191 days after therapy. These results provide a foundation for a potential one-and-done treatment for CVD.