DNA base editors have been harnessed as an exciting therapeutic platform for human diseases and are rapidly progressing into human clinical trials. However, persistent expression of base editors delivered via adeno-associated virus (AAV) poses concerns with specificity and immunogenicity. Here we develop selfinactivating base editor (siBE) systems with a negative feedback loop where one guide RNA (gRNA) targets the gene of interest and the other targets the deaminase domain itself. We demonstrate that siBE confers efficient on-target editing with time-dependent self-inactivation and increased editing specificity. For the in vivo utilization, we further employ the intein split approach to package siBE targeting mouse Angptl3 into AAV9. Systemic delivery of AAV9-siBE confer efficient editing of Angptl3 in liver, resulting in reduced serum levels of ANGPTL3, triglyceride and total cholesterol, with the active base editor undetectable at 8 weeks after administration. These self-inactivating base editing systems are highly promising for future therapeutic applications.