In vivo architectonic stability of fully de novo designed protein-only nanoparticles.
The fully de novo design of protein building blocks for self-assembling as functional nanoparticles is a challenging task in emerging nanomedicines, which urgently demand novel, versatile, and biologically safe vehicles for imaging, drug delivery, and gene therapy. While the use of viruses and virus-like particles is limited by severe constraints, the generation of protein-only nanocarriers is progressively reachable by the engineering of protein-protein interactions, resulting in self-assembling functional building blocks. In particular, end-terminal cationic peptides drive the organization of structurally diverse protein species as regular nanosized oligomers, offering promise in the rational engineering of protein self-assembling. However, the in vivo stability of these constructs, being a critical issue for their medical applicability, needs to be assessed. We have explored here if the cross-molecular contacts between protein monomers, generated by end-terminal cationic peptides and oligohistidine tags, are stable enough for the resulting nanoparticles to overcome biological barriers in assembled form. The analyses of renal clearance and biodistribution of several tagged modular proteins reveal long-term architectonic stability, allowing systemic circulation and tissue targeting in form of nanoparticulate material. This observation fully supports the value of the engineered of protein building blocks addressed to the biofabrication of smart, robust, and multifunctional nanoparticles with medical applicability that mimic structure and functional capabilities of viral capsids.
Oncogenesis and Antitumor Drug Group, Biomedical Research Institute Sant Pau (IIB-SantPau) , Hospital de la Santa Creu i Sant Pau, C/Sant Antoni Maria Claret, 167, 08025 Barcelona, Catalonia, Spain.
María Virtudes
MV
Céspedes
Ugutz
U
Unzueta
Witold
W
Tatkiewicz
Alejandro
A
Sánchez-Chardi
Oscar
O
Conchillo-Solé
Patricia
P
Álamo
Zhikun
Z
Xu
Isolda
I
Casanova
José Luis
JL
Corchero
Mireia
M
Pesarrodona
Juan
J
Cedano
Xavier
X
Daura
Imma
I
Ratera
Jaume
J
Veciana
Neus
N
Ferrer-Miralles
Esther
E
Vazquez
Antonio
A
Villaverde
Ramón
R
Mangues
D000818:Animals; D002213:Capsid / Q000737:chemistry; D002412:Cations; D016503:Drug Delivery Systems; D005260:Female; D005818:Genetic Engineering; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D007668:Kidney / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D018625:Microscopy, Atomic Force; D046529:Microscopy, Electron, Transmission; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011506:Proteins / Q000737:chemistry*; D055672:Static Electricity
D002412:Cations; D008024:Ligands; D010455:Peptides; D011506:Proteins; D049452:Green Fluorescent Proteins; D006639:Histidine