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WIREs Nanomed Nanobiotechnol
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Protein crystal based materials for nanoscale applications in medicine and biotechnology

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The porosity, order, biocompatibility, and chirality of protein crystals has motivated interest from diverse research domains including materials science, biotechnology, and medicine. Porous protein crystals have the unusual potential to organize guest molecules within highly ordered scaffolds, enabling applications ranging from biotemplating and catalysis to biosensing and drug delivery. Significant research has therefore been directed toward characterizing protein crystal materials in hopes of optimizing crystallization, scaffold stability, and application efficacy. In this overview article, we describe recent progress in the field of protein crystal materials with special attention given to applications in nanomedicine and nanobiotechnology. This article is categorized under: Biology‐Inspired Nanomaterials > Protein and Virus‐Based Structures Therapeutic Approaches and Drug Discovery > Emerging Technologies Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials
Various protein structures (top) and their corresponding crystal scaffolds (bottom) illustrating the diversity of pore sizes and geometries within this class of material; boxes delineate unit cells; scale bars: 20 nm. (a) Tetragonal hen egg white lysozyme (HEWL); PDB code: 2HTX. (b) CJ‐1 protein; PDB code: 5 W17. (c) Major tropism determinant P1 (Mtd‐P1) complexed with Pertactin extracellular domain (Prn‐E); PDB code: 2IOU. Images created using PyMOL v1.7.4.4, Schrödinger, LLC
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A selection of future applications for engineered protein crystals. Arranged in rough order of increasing economic value per microgram of crystal
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(a) SEM images of lysozyme crystals grown in 10‐μm wells. (Reprinted with permission from Wang et al. (). Copyright 2008 American Chemical Society) (b) Schematic of the OCER platform: (1) inlet ports; (2) extra inlet port for injecting analytic solutions; (3) passive zigzag micromixer; (4) serpentine channel for droplet storage and cross‐section depicting the layout of the solution‐storage array; (5) image of the structures located before and after the serpentine channel to prevent any mobile crystal/aggregate from being dragged by the injected solutions; (6) outlet port for the crystallization and cross‐linking solution to avoid any contamination of the sensing region; (7) multiple path configuration for the photonic detection system, allowing a large concentration range to be explored while maintaining the absorbance linear range; (8) 2D microlenses with air mirrors along the interrogation channel; (9) outlet port for the product solutions. (c) Operation of the solution trapping system during the injection of a green dyed solution. The meniscus of the flowing solution is observed when emptying the microfluidic device, while the solution trapping system retains nanoliter‐sized droplets in the microwell array. (d) Lipase crystals obtained in the OCER platform and (e) after being cross‐linked with glutaraldehyde. (Reprinted with permission from Conejero‐Muriel et al. (). Copyright 2016 American Chemical Society)
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(a) Bioluminescence intensity in the luciferase reporter assay for evaluation of NF‐κB activity of HEK293/κB‐Fluc cells in the presence of 1.0 ng/mL TNF‐α after incubation with PBS buffer (as control), Ru∙CL‐HEWL, Ru·HEWL, CORM‐2, and CL‐HEWL for 24 h. (Reprinted with permission from Tabe et al. (). Copyright 2015 American Chemical Society) (b) Luminescence intensity in the luciferase reporter assay for the evaluation of NF‐κB activity of HEK293/κB‐Fluc cells in the presence of 10 ng/mL TNF‐α after incubation for 12 hr with Mn·HTPhC, Mn·WTPhC, MnCO5Br and HTPhC, with the light irradiation for 20 min (white), 10 min (dot), 5 min (slashed) and without the light irradiation (black). (Reprinted with permission from Tabe et al. (). Copyright 2016 Royal Society of Chemistry) (b) Distribution of FITC‐labeled lysozyme crystals in a PCL nonwoven prepared using ~2 μm lysozyme crystals, a 25% PCL solution, and a drug loading of 5%. (Reprinted with permission from Puhl et al. (). Copyright 2014 American Chemical Society)
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(a) Schematic representation of LeX immobilization on the surface of PhC: (i) cysteine residues of PhC modified with propargyl maleimide; (ii) acetylene moieties modified with LeX‐azide via copper‐catalyzed azide‐alkyne cycloaddition; (iii) antibody–antigen reaction on the surface of modified PhCs. (Reprinted with permission from Abe et al. (). Copyright 2014 Chemical Society of Japan) (b) Schematic representations for directing His‐tagged fluorophore guests to protein crystals: (i) on the surface after crystal formation, (iii) within the crystal during formation, or (v) at both the surface and within crystals. (ii, iv, vi) Bright‐field (left) and confocal (right) microscopy images. (Reprinted with permission from Nepal et al. (). Copyright 2016 American Chemical Society) (c) Confocal imaging of an interior plane within a highly porous CJ crystal, demonstrating spatially segregated macromolecular guests (mNeonGreen and mCherry) immobilized with Zn2+. (Reprinted with permission from Huber et al. (). Copyright 2017 Royal Society of Chemistry)
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(a) Disulfide linkages within a porous protein crystal scaffold. (Reprinted with permission from Quistgaard (). Copyright 2014 Royal Society of Chemistry) (b) Schematic of zinc mediated crystal formation of MBPPhen2 illustrating resultant lattice porosity. (Reprinted with permission from Radford et al. (). Copyright 2010 Royal Society of Chemistry) (c) Schematic of metal mediated coiled‐coil crystal assembly. (Reprinted with permission from Nepal et al. (). Copyright 2016 American Chemical Society)
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(a) Aldehydes of varying length. (b) Formaldehyde cross‐linking leads to a stable final conjugation product. (c) Monomeric glutaraldehyde cross‐linking results in unstable Schiff base formation unless a reducing agent (e.g., NaCNBH3) is added—Leading to reductive amination
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(a) Co‐diffusion of fluorescein (left) and rhodamine B (right) in a cross‐linked HEWL crystal. (b) the pore diffusion coefficient (Dp) is related to the ratio of guest substrate diameter (ds) to pore diameter (dp). (a) and (b). (Reprinted with permission from Cvetkovic et al. (). Copyright 2005 American Chemical Society) (c) The adsorbed guest concentration (q) causes occlusion of the scaffold pore leading to attenuation of Dp. (Reprinted with permission from Hartje et al. (). Copyright 2017 American Chemical Society)
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(a) HDFa cell viability under varying concentrations of cross‐linked CJ crystal materials; error bars: standard deviation, n = 3. (b) HDFa cell viability under varying concentrations of fragmented HEWL protein crystal materials; error bars: standard deviation, n = 3. (c) HDFa cells incubated with 400 μg/mL protein crystal material; top: green fluorescent live cell stain (calcein); bottom: red fluorescent dead cell stain (ethidium homodimer); left: CJ/GA, scale bar: 100 μm; right: CJ/EDC, scale bar: 300 μm. (d) MV‐4‐11 cell viability when incubated with various protein crystal materials at a concentration of 400 μg/mL; error bars: Standard deviation, n = 3. (Reprinted with permission from Hartje et al. (). Copyright 2018 American Chemical Society)
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EDC reacts with carboxylic acids to create an active‐ester intermediate. In the presence of an amine nucleophile, a zero‐length amide bond is formed with release of an isourea by‐product
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Functional groups associated with ionizable amino acids
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A protein crystallization phase diagram based on varied protein and precipitant concentrations. Three commonly used crystallization methods are highlighted showing the path each method takes to produce crystals. Note that all paths need to reach the same destination, namely the nucleation zone, after which they make their way through the metastable zone, where crystal growth takes place, and eventually arrive at the solubility curve. • represents possible starting conditions. (a) Dialysis. (b) Vapor diffusion. (c) Batch crystallization. (Reprinted with permission from Chayen (). Copyright 1998 International Union of Crystallography)
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Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials
Therapeutic Approaches and Drug Discovery > Emerging Technologies
Biology-Inspired Nanomaterials > Protein and Virus-Based Structures

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