Abstract Biomaterials are widely employed across diverse biomedical applications and represent an attractive strategy to explore how extracellular matrix components influence cellular response. In this study, the previously developed streptavidin platforms is aimed to use to investigate the role of glycosaminoglycans (GAGs) in bone morphogenetic protein 2 (BMP2) signaling. However, it is observed that the interpretation of findings is skewed due to the GAG‐unrelated, non‐specific binding of BMP2 on components of biomaterials. Non‐specific adsorption of proteins is a recurrent and challenging issue for biomaterial studies. Despite the initial incorporation of anti‐fouling polyethylene glycol (PEG) chains within biomaterials, the residual non‐specific BMP2 adsorption still triggered BMP2 signaling within the same range as conditions of interest. The various options are explored to prevent BMP2 non‐specific adsorption and a successful blocking condition involving a combination of bovine serum albumin and trehalose are identified. Furthermore, the effect of this blocking step improved when using gold platforms instead of glass, particularly with Chinese hamster ovary (CHO) cells. With this specific example, it is suggested that non‐specific adsorption of BMPs on biomaterials may be a general concern – often undetected by classical surface‐sensitive techniques – that needs to be addressed to better interpret cellular responses.