Engineering protein nanocages as carriers for biomedical applications

Bhaskar, Sathyamoorthy; Lim, Sierin

S Bhaskar and S Lim challenging to construct by the assembly of organic and inorganic subunits. The enormous size of existing protein structural databases could aid the design of a diverse class of self-assembling structures. 35 Hybrid protein scaffolds To expand their applications in diagnostics/therapeutics and to modulate the immune response, protein nanocages have been conjugated with other moieties (i.e. sugar, lipid, nucleotides and polymer) that result in hybrid protein scaffolds. Synthetic polymer conjugates of viruses, such as tobacco mosaic virus, adenovirus, and cowpea mosaic virus, are the most widely reported hybrid conjugates of protein scaffolds. 38 Lucon et al. 39 synthesized poly(2-aminoethyl methacrylate) from the interior of P22 viral capsids through atom-transfer radical polymerization, producing particles with increased loading capacity for magnetic resonance imaging (MRI) contrast agents, Gd-DTPA. 39 Protein nanocages could be enclosed within a polymeric shell attached covalently to the external surface of the protein core. 2 Polymerizable vinyl groups are grafted to the protein, and further polymerization with crosslinkers and monomers favors the formation of a thin polymer coat around the protein. Such strategies are designed to produce protein nanocages with a non-degradable or degradable polymeric shell for designated purposes ( Figure 8 ). 2 Similarly, introducing a certain class of 'smart polymers' could impart stimuliresponsive properties to protein nanocages. 28 Smart polymers are designed to be sensitive to external factors such as heat, pH, magnetic field and enzymatic degradation, as well as other microenvironmental changes. For instance, pNIPAAm (poly(N-isopropylacrylamide)) is a well-known temperature-sensitive polymer that undergoes a reversible phase change, losing its water solubility above the lower critical solution temperature. 28 Matsumoto et al. 28 produced novel biohybrid nanoparticles through covalent linkage of pNIPAAm to recombinant CP-MVP (cysteine-rich 12-amino-acid peptide to the N-terminus of the MVP) vaults ( Figure 9 ). 28 The resulting polymerized particles were thermally responsive as expected. Although synthetic polymer-protein nanocage hybrids have been widely explored, reports on sugar, polysaccharide, nucleotide or lipid modifications are limited.