Elevated low-density lipoprotein cholesterol (LDL-C) is one of the major contributors to cardiovascular heart disease (CHD)， the leading cause of death worldwide. Due to severe side effects of statins， alternative treatment strategies are required for statin-intolerant patients. Monoclonal antibodies (mAbs) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) have shown great efficacy in LDL-C reduction. Limitations for this approach include the need for multiple injections as well as increased costs associated with patient management. Here， we engineered a DNA-encoded mAb (DMAb) targeting PCSK9 (daPCSK9)， as an alternative approach to protein-based lipid-lowering therapeutics， and we characterized its expression and activity. A single intramuscular administration of mouse daPCSK9 generated expression in?vivo for over 42?days that corresponded with a substantial decrease of 28.6% in non-high-density lipoprotein cholesterol (non-HDL-C) and 10.3% in total cholesterol by day 7 in wild-type mice. Repeated administrations of the DMAb plasmid led to increasing expression， with DMAb levels of 7.5?μg/mL at day 62. daPCSK9 therapeutics may provide a novel， simple， less frequent， cost-effective approach to reducing LDL-C， either as a stand-alone therapy or in combination with other LDL-lowering therapeutics for synergistic effect.