AbstractBiomimetics offers excellent prospects for design a novel generation of improved biomaterials. Here the controlled integration of graphene oxide (GO) derivatives with a 3D marine spongin (MS) network is explored to nanoengineer novel smart bio‐based constructs for bone tissue engineering. The results point out that 3D MS surfaces can be homogeneously coated by layer‐by‐layer (LbL) assembly of oppositely charged polyethyleneimine (PEI) and GO. Notably, the GOPEI@MS bionanocomposites present a high structural and mechanical stability under compression tests in wet conditions (shape memory). Dynamic mechanically (2 h of sinusoidal compression cyclic interval (0.5 Hz, 0–10% strain)/14 d) stimulates GOPEI@MS seeded with osteoblast (MC3T3‐E1), shows a significant improvement in bioactivity, with cell proliferation being two times higher than under static conditions. Besides, the dynamic assays show that GOPEI@MS bionanocomposites are able to act as mechanical stimulus‐responsive scaffolds able to resemble physiological bone extracellular matrix (ECM) requirements by strongly triggering mineralization of the bone matrix. These results prove that the environment created by the system cell‐GOPEI@MS is suitable for controlling the mechanisms regulating mechanical stimulation‐induced cell proliferation for potential in vivo experimentation.