Limited healthcare capacity highlights the needs of integrated sensing systems for personalized health-monitoring. However, only limited sensors can be employed for point-of-care applications, emphasizing the lack of a generalizable sensing platform. Here, we report a metal organic framework (MOF) ZIF-90-ZnO-MoS2 nanohybrid-based integrated electrochemical liquid biopsy (ELB) platform capable of direct profiling cancer exosomes from blood. Using a bottom-up approach for sensor design, a series of critical sensing functions is considered and encoded into the MOF material interface by programming the material with different chemical and structural features. The MOF-based ELB platform is able to achieve one-step sensor fabrication, target isolation, nonfouling and high-sensitivity sensing, direct signal transduction, and multiplexed detection. We demonstrated the capability of the designed sensing system on differentiating cancerous groups from healthy controls by analyzing clinical samples from lung cancer patients, providing a generalizable sensing platform.