Background: Bacterial inclusion bodies (IBs), mechanically stable, submicron protein particles of 50–500 nm dramatically favor mammalian cell spread when used for substrate surface decoration. The mechanisms supporting fast colonization of IB-modified surfaces have not yet been identified. Results: This study provides evidence of mechanotransduction-mediated stimulation of mammalian cell proliferation on IB-decorated surfaces, as observed by the enhanced phosphorylation of the signal-regulated protein kinase and by the dramatic emission of filopodia in the presence of IBs. Interestingly, the results also show that IBs are highly bioadhesive materials, and that mammalian cell expansion on IBs is synergistically supported by both enhanced adhesion and mechanical stimulation of cell division. Discussion: The extent in which these events influence cell growth depends on the particular cell line response but it is also determined by the genetic background of the IB-producing bacteria, thus opening exciting possibilities for the fine tailoring of protein nanoparticle features that are relevant in tissue engineering. Original submitted: 7 February 2011; Revised submitted: 7 April 2011