Protein nanoparticles are nontoxic, tuneable cell stressors

Nanoparticle-cell interactions can promote cell toxicity and stimulate particular behavioral patterns, but cell responses to protein nanomaterials have been poorly studied. By repositioning oligomerization domains in a simple, modular self-assembling protein platform, we have generated closely related but distinguishable homomeric nanoparticles. Composed by building blocks with modular domains arranged in different order, they share amino acid composition. These materials, once exposed to cultured cells, are differentially internalized in absence of toxicity and trigger distinctive cell adaptive responses, monitored by the emission of tubular filopodia and enhanced drug sensitivity. The capability to rapidly modulate such cell responses by conventional protein engineering reveals protein nanoparticles as tuneable, versatile and potent cell stressors for cell-targeted conditioning. Protein nanoparticles have been unexpectedly found as able to induce adaptive responses in exposed cells, involving morphological and functional changes, in absence of toxicity. These responses can be tuned by conventional protein engineering of the building blocks and adapted and exploited in the context of molecular therapies.