Protein cages and synthetic polymers: a fruitful symbiosis for drug delivery applications, bionanotechnology and materials science

Abstract

Protein cages are hollow protein nanoparticles, such as viral capsids, virus-like particles, ferritin, heat-shock proteins and chaperonins. They have well-defined capsule-like structures with a monodisperse size. Their protein subunits can be modified by genetic engineering at predetermined positions, allowing for example site-selective introduction of attachment points for functional groups, catalysts or targeting ligands on their outer surface, in their interior and between subunits. Therefore, protein cages have been extensively explored as functional entities in bionanotechnology, as drug-delivery or gene-delivery vehicles, as nanoreactors or as templates for the synthesis of organic and inorganic nanomaterials. The scope of functionalities and applications of protein cages can be significantly broadened if they are combined with synthetic polymers on their surface or within their interior. For example, PEGylation reduces the immunogenicity of protein cage-based delivery systems and active targeting ligands can be attached via polymer chains to favour their accumulation in diseased tissue. Polymers within protein cages offer the possibility of increasing the loading density of drug molecules, nucleic acids, magnetic resonance imaging contrast agents or catalysts. Moreover, the interaction of protein cages and polymers can be used to modulate the size and shape of some viral capsids to generate structures that do not occur with native viruses. Another possibility is to use the interior of polymer cages as a confined reaction space for polymerization reactions such as atom transfer radical polymerization or rhodium-catalysed polymerization of phenylacetylene. The protein nanoreactors facilitate a higher degree of control over polymer synthesis. This review will summarize the hybrid structures that have been synthesized by polymerizing from protein cage-bound initiators, by conjugating polymers to protein cages, by embedding protein cages into bulk polymeric materials, by forming two- and three-dimensional crystals of protein cages and dendrimers, by adsorbing proteins to the surface of materials, by layer-by-layer deposition of proteins and polyelectrolytes and by encapsulating polymers into protein cages. The application of these hybrid materials in the biomedical context or as tools and building blocks for bionanotechnology, biosensing, memory devices and the synthesis of materials will be highlighted. The review aims to showcase recent developments in this field and to suggest possible future directions and opportunities for the symbiosis of protein cages and polymers.

Rational Design of Nanocarriers for Intracellular Protein Delivery

“…[17] For example, Cao and coworkers applied genetic method to generate human ferritin H-chain protein (FTH1)-based NPs that fused with epidermal growth factor receptor (EGF-FTH1). The diameter of cages is usually less than 30 nm which can exit the vasculature, permeate tissue, and enter the lymphatic system by passive diffusion.…”

“…[15] A wide array of nanocarrier systems including lipid, polymers, protein complex, inorganic materials have been shown to be promising strategies. [16][17][18][19] In these strategies, different methods are applied to load the delivery system with the targeted proteins, such as genetic modification, physical adsorption, or chemical conjugation. In addition, these protein delivery systems based on NPs could be engineered with various ligands for targeting to the desired subcellular compartments like cytosol, nucleus and mitochondria.…”

“…In the protein cage-based NPs, most protein drugs could be localized on the surface of cages via either covalent bioconjugation or genetic fusion. [17] For example, Cao and coworkers applied genetic method to generate human ferritin H-chain protein (FTH1)-based NPs that fused with epidermal growth factor receptor (EGF-FTH1). [236] Cell-based results demonstrated that this EGF-FTH1 NPs could specifically bind to breast cancer MCF-7 cells and MDA-MB-231 cells but not normal breast epithelial MCF-10A cells.…”

Photochemistry for Well‐Defined Polymers in Aqueous Media: From Fundamentals to Polymer Nanoparticles to Bioconjugates

“…In addition to oxygen‐tolerant polymerization, photo‐PISA has been used to create protein‐based self‐assembled nanoparticles using BSA as a model protein . This area of research has attracted interest due to potential applications, biocompatibility, and degradability of protein nanoparticles . Traditionally, these nanoparticles are formed by the conjugation of hydrophobic polymers to hydrophilic proteins to induce direct self‐assembly to form spheres, worms, or vesicles in aqueous solution .…”

“…[151] This area of research has attracted interest due to potential applications, biocompatibility, and degradability of protein nanoparticles. [152][153][154] Traditionally, these nanoparticles are formed by the conjugation of hydrophobic polymers to hydrophilic proteins to induce direct self-assembly to form spheres, worms, or vesicles in aqueous solution. [155,156] Huang and co-workers used site-specific modified BSA as a star macro-RAFT in aqueous media and subsequently grew HPMA polymer chains, utilizing a "grafting-from" approach, as seen in Scheme 11.…”