Engineering Self-Assembling Protein Nanoparticles for Therapeutic Delivery

Abstract

Despite remarkable advances over the past several decades, many therapeutic nanomaterials fail to overcome major in vivo delivery barriers. Controlling immunogenicity, optimizing biodistribution, and engineering environmental responsiveness are key outstanding delivery problems for most nanotherapeutics. However, notable exceptions exist including some lipid and polymeric nanoparticles, some virus-based nanoparticles, and nanoparticle vaccines where immunogenicity is desired. Self-assembling protein nanoparticles offer a powerful blend of modularity and precise designability to the field, and have the potential to solve many of the major barriers to delivery. In this review, we provide a brief overview of key designable features of protein nanoparticles and their implications for therapeutic delivery applications. We anticipate that protein nanoparticles will rapidly grow in their prevalence and impact as clinically relevant delivery platforms.

Ferritin nanocages as efficient nanocarriers and promising platforms for COVID-19 and other vaccines development

“…Simple ferritin nanoparticle constructs are successfully produced in E. coli and then purified, but bacteria lack the ability to express glycosylated proteins and/or complex antigens. Thus, modified ferritin nanoparticles that require mammalian post-translational modifications must be produced in eukaryotic cells [ 73 ]. The simple recombinant ferritins derived from bacteria are typically synthesized by transforming the cells with vectors that express H and/or L subunits under a strong and inducible promotor [ 74 ].…”

“…A protein of interest (POI) may be conjugated to ferritin's surface through genetic fusion of the gene encoding the POI to the N-terminal end of ferritin subunits, which are exposed to the protein's outer surface, using established recombinant DNA technologies for subsequent production in a chosen expression system [ 115 ]. From the expression of simple peptides to complex trimers, genetic fusion of POI on ferritin's external surface has had wide applications in the field of vaccine development, including the search for vaccines against influenza [ [116] , [117] , [118] ] Epstein-Barr virus [ 119 ], hepatitis C [ 73 , 120 , 121 ], HIV-1 [ 73 , 122 ], Lyme [ 123 ], RSV [ 124 ], and SARS-CoV-2 [ [125] , [126] , [127] , [128] , [129] , [130] , [131] , [132] , [133] ] which will be discussed in a later section. A pitfall to expressing a protein of interest on ferritin's exterior through genetic fusion, however, is that care must be taken to recombinantly express antigens in a way that does not impair their stability or conformation, nor impair ferritin's inter-subunit interactions during the self-assembly process [ 75 ].…”

“…This is corroborated by a recent study demonstrating that a minimum of 20–25 epitopes spaced by 5–10 nm are required to elicit sufficient B-cell activation [ 164 ]. Other studies have demonstrated that epitope-protein nanoparticles elicit stronger immune responses compared to soluble antigens [ 73 ]. Furthermore, intramuscular injections of spherical protein nanoparticles have been shown to have the ideal shape and size (~ 20–150 nm in diameter) to be taken up by peripheral or lymph node dendritic cells [ 165 ].…”

“…Ferritin has also been used as an antigen display platform in the search for a safe and effective vaccine against HIV, particularly focusing on the viral gp120 glycoprotein, the major component of the viral envelope [ 73 ]. Zhou et al demonstrated that grafting of a glycopeptide from the variable region 3 on gp120 onto ferritin nanoparticles resulted in successful recognition by neutralizing antibodies from three different donors whereas the free antigen failed to be recognized.…”

Bioconjugate Chemistry: Enabling Innovation and Fostering Community at the Nexus of Synthetic and Biological Research

“…11−13 These and many past, current, and future innovations in bioconjugates coupled with directed evolution, artificial intelligence, and automation is shepherding in a new era for improving global healthcare, agriculture, and the environment. 14,15 I am incredibly grateful and very excited to be a part of this growing field, community, and journal as the next leader of Bioconjugate Chemistry, a leading venue for publication of transformative research at the nexus of chemical and biological science and engineering. Along with publication, building trust through inclusive communication across our global Bioconjugate Chemistry community is an important effort that is aligned with the journal and my leadership goals.…”