An appropriate sensor surface biofunctionalization is the most critical and commonly neglected step to fully achieve a highly sensitive and accurate label-free biosensor. We investigate, develop, and optimize novel surface chemistry methodologies to promote surface accessibility and enhance efficiency, which maximize the analytical performance of our biosensors in terms of sensitivity, selectivity, and reproducibility, enabling direct analysis in complex matrices, such as blood serum or plasma or urine. Currently, we also explore the incorporation of novel 2D materials (graphene, MOFs, etc.) as sensor interfaces that will boost and promote new applications of our sensor technologies.