Probing the Biosafety of Implantable Artificial Secretory Granules for the Sustained Release of Bioactive Proteins

Patricia Álamo, Eloi Parladé, Marianna T.P. Favaro, Alberto Gallardo, Rosa Mendoza, Luís C.S. Ferreira, Nerea Roher, Ramón Mangues*, Antonio Villaverde*, Esther Vázquez

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

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Among bio-inspired protein materials, secretory protein microparticles are of clinical interest as self-contained, slow protein delivery platforms that mimic secretory granules of the human endocrine system, in which the protein is both the drug and the scaffold. Upon subcutaneous injection, their progressive disintegration results in the sustained release of the building block polypeptides, which reach the bloodstream for systemic distribution and subsequent biological effects. Such entities are easily fabricated in vitro by Zn-assisted cross-molecular coordination of histidine residues. Using cationic Zn for the assembly of selected pure protein species and in the absence of any heterologous holding material, these granules are expected to be nontoxic and therefore adequate for different clinical uses. However, such presumed biosafety has not been so far confirmed and the potential protein dosage threshold not probed yet. By selecting the receptor binding domain (RBD) from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein as a model protein and using a mouse lab model, we have explored the toxicity of RBD-made secretory granules at increasing doses up to ∼100 mg/kg of animal weight. By monitoring body weight and biochemical blood markers and through the histological scrutiny of main tissues and organs, we have not observed systemic toxicity. Otherwise, the bioavailability of the material was demonstrated by the induction of specific antibody responses. The presented data confirm the intrinsic biosafety of artificial secretory granules made by recombinant proteins and prompt their further clinical development as self-contained and dynamic protein reservoirs.

Original languageEnglish
Pages (from-to)39167-39175
Number of pages9
JournalACS Applied Materials and Interfaces
Issue number33
Publication statusPublished - 23 Aug 2023


  • drug delivery
  • protein engineering
  • protein materials
  • recombinant protein
  • self-assembling
  • Humans
  • Prostheses and Implants
  • Containment of Biohazards
  • COVID-19
  • Delayed-Action Preparations/pharmacology
  • SARS-CoV-2
  • Animals
  • Disease Models, Animal
  • Protein engineering
  • Protein materials
  • Drug delivery
  • Recombinant protein
  • Self-assembling


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