The continuous, real-time monitoring of specific analytes in situ in biological fluids would provide personalized, high-precision pharmacokinetic information for the goal of precision medicine. Due to their conformationally linked signaling mechanism, electrochemical aptamer-based (E-AB) sensors are promising candidates for accurate measurements in such complex media. They suffer, however, from severe baseline drift when interrogated continuously and in real-time manner. In response, here, we investigate a couple of self-assembled monolayers in the application of E-AB sensors, achieving the improvement of their baseline stability and simultaneous modulation of sensor performance, e.g., target affinity and specificity.