Hexahistidine-tagged proteins can be clustered by divalent cations into self-containing, dynamic protein depots at the microscale, which under physiological conditions leak functional protein. While such protein granules show promise in clinics as time-sustained drug delivery systems, little is known about how the nature of their components, that is, the protein and the particular cation used as cross-linker, impact on the disintegration of the material and on its secretory performance. By using four model proteins and four different cation formulations to control aggregation, we have here determined a moderate influence of the used cation and a potent impact of some protein properties on the release kinetics and on the final fraction of releasable protein. In particular, the electrostatic charge at the amino terminus and the instability and hydropathicity indexes determine the disintegration profile of the depot. These data offer clues for the fabrication of efficient and fully exploitable secretory granules that being biocompatible and chemically homogenous allow their tailored use as drug delivery platforms in biological systems.

Original languageEnglish
Article number126164
Pages (from-to)126164
Number of pages8
JournalInternational journal of biological macromolecules
Early online date6 Aug 2023
Publication statusPublished - 1 Oct 2023


  • Building blocks
  • Drug delivery system
  • Microparticles
  • Recombinant proteins
  • Secretory amyloids
  • Time sustained drug release


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