Bacterial mimetics of endocrine secretory granules as immobilized in vivo depots for functional protein drugs

Céspedes MV, Fernández Y, Unzueta U, Mendoza R, Seras-Franzoso J, Sánchez-Chardi A, Álamo P, Toledo-Rubio V, Ferrer-Miralles N, Vazquez E, Schwartz S Jr, Abasolo I, Corchero JL, Mangues R, Villaverde A

Sci Rep. 2016 Oct 24;6:35765.


In the human endocrine system many protein hormones including urotensin, glucagon, obestatin, bombesin and secretin, among others, are supplied from amyloidal secretory granules. These granules form part of the so called functional amyloids, which within the whole aggregome appear to be more abundant than formerly believed. Bacterial inclusion bodies (IBs) are non-toxic, nanostructured functional amyloids whose biological fabrication can be tailored to render materials with defined biophysical properties. Since under physiological conditions they steadily release their building block protein in a soluble and functional form, IBs are considered as mimetics of endocrine secretory granules. We have explored here if the in vivo implantation of functional IBs in a given tissue would represent a stable local source of functional protein. Upon intratumoral injection of bacterial IBs formed by a potent protein ligand of CXCR4 we have observed high stability and prevalence of the material in absence of toxicity, accompanied by apoptosis of CXCR4+ cells and tumor ablation. Then, the local immobilization of bacterial amyloids formed by therapeutic proteins in tumors or other tissues might represent a promising strategy for a sustained local delivery of protein drugs by mimicking the functional amyloidal architecture of the mammals’ endocrine system.