Abstract: Chronic infection of hepatitis B virus (HBV) is a severe public health problem because it affects millions of people worldwide and results in 600 thousand deaths from liver cirrhosis and hepatocarcinoma each year. Currently, no treatment is available to cure this disease. Here, we propose a synthetic immunity strategy to treat this disease. Specifically, minicircle DNA, an optimized non-viral vector, is used to express a group of engineered antibodies, of which the monoclonal antibodies act to neutralize the virus, while the bispecific antibodies (BsAbs) to render the resting Tlymphocytes the function of anti-HBV CTLs to eliminate HBV-infected hepatocytes. The two classes of antibodies work in concert to cure the disease as the host immune system eliminates the virus during recovering from acute infection. With the superior features in safety, transgene expression profile and cost-effectiveness, minicircle can be used to establish apowerful anti-HBV synthetic immunity to achieve this goal.