Immune cells can precisely recognize abnormal host cells or tumor cells or invading pathogens. The specificity of immune recognition is mainly dependent on a structure called immune synapse at the interface between lymphocytes and target cells. Immune synapse is formed based on the recruitment of various transmembrane molecules and lipid raft on the fluid lipid bilayer. In addition, densely lipid bilayer formed an antifouling surface to reduce intercellular adhesion and resist nonspecific protein adsorption further. Inspired by the phenomenon, we developed a fluid and antifouling electrochemical aptamer sensor for rare targets based on mixed self-assembled DNA tetrahedron and antifouling lipid bilayer on the gold electrode. The obtained biosensing platform has superior selectivity and sensitivity to target tumor cells, and exhibits excellent anti-protein properties and sensitivity in rare tumor cells detection in complex whole blood samples. The biosensor can also be applied to the detection of other targets, such as small molecule drugs in the blood.