The seemingly inevitable protein corona appears to be an insurmountable obstacle to wider application of functional nanomaterials in biotechnology. The accumulation of serum proteins can block targeting functionalities and alter the in vivo fate of these nanomaterials. Here we demonstrate a method to generate non-stick, robustly passivated functional nanoparticles (NPs) using a tailored silica coating. We apply agarose gel electrophoresis to sensitively evaluate protein binding to NPs with different surface chemistry. Using gel banding and retardation as a read-out for protein adsorption, we optimize the surface chemistry to yield a mixed charge surface which displays remarkable binding resistance to a wide range of serum proteins and nucleic acids. The hard silica shell also protects the functional NP core in harsh environments (down to pH 1) while still showing the ability to be targeted for cellular uptake with little or no non-specific binding.