Non-specific protein adsorption (NPA) is ubiquitous and generally considered a trigger for various biofoulings, adversely affecting diverse fields. Despite many approaches (generally polymer-based) available to combat NPA in a wide range of length scales, suppressing NPA in closed nanoscale spaces of emerging nanodevices such as nanofluidic devices remains a challenge due to the lack of suitable material and methodology to satisfy their ultra-small and closed features. In this study, a biomimetic, hydrosilane-functionalized 2-methacryloyloxyethyl phosphorylcholine (MPC) monomer material, which has tailored molecular characteristics and well-defined surface properties to overcome the challenges in the nanospaces, is elaborately designed and synthesized to form self-assembled, nanoscale, biomimetic coatings, enabling the efficient suppression of NPA in femtoliter-order, closed nanofluidic channels. The approach opens up a new path for exploring a strategic change of anti-biofouling coating from traditional polymer-based methodologies to a monomer-based methodology to overcome the challenge of suppressing NPA in closed nanospaces.