The aim of this study is to elucidate the functional mechanism of nanosilica-induced cell affinity for the normally attachment-fouling hydrogel substrates. Investigations were conducted in the following three major aspects: (1) environmental protein adsorption before cell contacts, which determines the presence of adhesive ligands; (2) integrin expression profile, which reflects the cell responses via surface receptor turning-over: and (3) vinculin activation and F-actin assembly which sketches the induced cytoskeletal organization posing for focal adhesion. The results indicate that the hybridized nanosilica additives are capable of arresting adhesive proteins from the environment. As binding ligands, such immobilized proteins activate alpha 5 beta 1-specific pathway for cell focal adhesion, but fail in invoking beta 3-participated signaling cascade. This partial activation enables modest amount of high-quality cell adhesion on the modified substrate, by which a conservative cell affinity is established on hydrogel matrices.