A Versatile Virus-Mimetic Engineering Approach for Concurrent Protein Nanocage Surface-Functionalization and Cargo Encapsulation

TY - JOUR

T1 - A Versatile Virus-Mimetic Engineering Approach for Concurrent Protein Nanocage Surface-Functionalization and Cargo Encapsulation

AU - Sheng, Yujie

AU - Chen, Zilong

AU - Cherrier, Mickael V.

AU - Martin, Lydie

AU - Bui, Tam T.T.

AU - Li, Wei

AU - Lynham, Steven

AU - Nicolet, Yvain

AU - Ebrahimi, Kourosh H.

N1 - © 2024 The Authors. Small published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

PY - 2024/8/1

Y1 - 2024/8/1

N2 - Naturally occurring protein nanocages like ferritin are self-assembled from multiple subunits. Because of their unique cage-like structure and biocompatibility, there is a growing interest in their biomedical use. A multipurpose and straightforward engineering approach does not exist for using nanocages to make drug-delivery systems by encapsulating hydrophilic or hydrophobic drugs and developing vaccines by surface functionalization with a protein like an antigen. Here, a versatile engineering approach is described by mimicking the HIV-1 Gap polyprotein precursor. Various PREcursors of nanoCages (PREC) are designed and created by linking two ferritin subunits via a flexible linker peptide containing a protease cleavage site. These precursors can have additional proteins at their N-terminus, and their protease cleavage generates ferritin-like nanocages named protease-induced nanocages (PINCs). It is demonstrated that PINC formation allows concurrent surface decoration with a protein and hydrophilic or hydrophobic drug encapsulation up to fourfold more than the amount achieved using other methods. The PINCs/Drug complex is stable and efficiently kills cancer cells. This work provides insight into the precursors’ design rules and the mechanism of PINCs formation. The engineering approach and mechanistic insight described here will facilitate nanocages’ applications in drug delivery or as a platform for making multifunctional therapeutics like mosaic vaccines.

AB - Naturally occurring protein nanocages like ferritin are self-assembled from multiple subunits. Because of their unique cage-like structure and biocompatibility, there is a growing interest in their biomedical use. A multipurpose and straightforward engineering approach does not exist for using nanocages to make drug-delivery systems by encapsulating hydrophilic or hydrophobic drugs and developing vaccines by surface functionalization with a protein like an antigen. Here, a versatile engineering approach is described by mimicking the HIV-1 Gap polyprotein precursor. Various PREcursors of nanoCages (PREC) are designed and created by linking two ferritin subunits via a flexible linker peptide containing a protease cleavage site. These precursors can have additional proteins at their N-terminus, and their protease cleavage generates ferritin-like nanocages named protease-induced nanocages (PINCs). It is demonstrated that PINC formation allows concurrent surface decoration with a protein and hydrophilic or hydrophobic drug encapsulation up to fourfold more than the amount achieved using other methods. The PINCs/Drug complex is stable and efficiently kills cancer cells. This work provides insight into the precursors’ design rules and the mechanism of PINCs formation. The engineering approach and mechanistic insight described here will facilitate nanocages’ applications in drug delivery or as a platform for making multifunctional therapeutics like mosaic vaccines.

KW - drug encapsulation

KW - ferritin

KW - mosaic nanocage

KW - PINC

KW - precursor of nanocages

KW - protein nanocages

UR - http://www.scopus.com/inward/record.url?scp=85192528916&partnerID=8YFLogxK

U2 - 10.1002/smll.202310913

DO - 10.1002/smll.202310913

M3 - Article

AN - SCOPUS:85192528916

SN - 1613-6810

VL - 20

JO - Small

JF - Small

IS - 31

M1 - 2310913

ER -