Rational Engineering of a Designed Protein Cage for siRNA Delivery

Edwardson, Thomas G. W.; Mori, Takeo; Hilvert, Donald

doi:10.1021/jacs.8b06442

Cited by 96 publications

(148 citation statements)

References 56 publications

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“…9), which also revealed that Nile Red was distributed throughout the cell. Based on the intracellular trafficking of OP cages, the majority of which localize in endosomes 22 , this result suggests that the Nile Red cargo escapes from the capsids after internalization and shuttles to hydrophobic environments in the cell. To test this hypothesis, Atto425-labeled OP capsids were used ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 98%

Two-tier supramolecular encapsulation of small molecules in a protein cage

Tetter

Hilvert

2020

Nat Commun

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Expanding protein design to include other molecular building blocks has the potential to increase structural complexity and practical utility. Nature often employs hybrid systems, such as clathrin-coated vesicles, lipid droplets, and lipoproteins, which combine biopolymers and lipids to transport a broader range of cargo molecules. To recapitulate the structure and function of such composite compartments, we devised a supramolecular strategy that enables porous protein cages to encapsulate poorly water-soluble small molecule cargo through templated formation of a hydrophobic surfactant-based core. These lipoprotein-like complexes protect their cargo from sequestration by serum proteins and enhance the cellular uptake of fluorescent probes and cytotoxic drugs. This design concept could be applied to other protein cages, surfactant mixtures, and cargo molecules to generate unique hybrid architectures and functional capabilities.

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Section: Resultsmentioning

confidence: 98%

Two-tier supramolecular encapsulation of small molecules in a protein cage

Tetter

Hilvert

2020

Nat Commun

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“…Another study used the octahedral cages as a starting point and introduced positively charged amino acids to facilitate siRNA uptake. Interestingly, these containers were able to deliver their cargo to mammalian cells and induce RNA interference (RNAi) and knockdown gene expression . Overall, artificial protein containers are a promising scaffold for delivery applications and material design.…”

Section: Novel Protein Architecturesmentioning

confidence: 99%

Multi‐Component Self‐Assembly of Proteins and Inorganic Particles: From Discrete Structures to Biomimetic Materials

Künzle

Lach

Beck

2019

Israel Journal of Chemistry

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Due to their defined structure, proteins are suitable building blocks for the bottom‐up construction of multi‐component materials. Especially protein containers, with their inherent cavity, can be used to encapsulate synthetic components such as inorganic nanoparticles. This way, multi‐component discrete structures can be assembled. With recent advances in computational protein design, novel protein containers were successfully created, with a high potential for application in biomedicine and materials research. Moreover, engineered protein containers offer a unique building block for the self‐assembly of three‐dimensional materials. They combine the molecular precision of proteins with nanoscale dimensions. Designed interactions lead to novel protein scaffolds. In addition, nanoparticles encapsulated inside the container cavity introduce orthogonal functionality, important for the realization of nanostructured biomimetic materials with emergent properties.

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“…Protein-based nanoparticles, both natural and designed, have gained increasing attention as promising materials for a wide variety of applications in nanotechnology, nanomedicine, and materials science. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] The growing interest in proteinbased materials has stimulated interest in designing new protein assemblies of various architectures that incorporate structural and functional properties that extend beyond those found in Nature. The assembly of protein building blocks (PBB) into large-scale cage-like structures has been accomplished through different approaches; these include the design of new protein-protein interfaces, [16][17][18] the fusion of oligomeric protein domains, 19,20 and by using de novo-designed oligomeric coiled coils to connect together larger, natural proteins.…”

Section: Introductionmentioning

confidence: 99%

Metal‐dependent assembly of a protein nano‐cage

Cristie‐David

Marsh

2019

Protein Science

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Short, alpha‐helical coiled coils provide a simple, modular method to direct the assembly of proteins into higher order structures. We previously demonstrated that by genetically fusing de novo–designed coiled coils of the appropriate oligomerization state to a natural trimeric protein, we could direct the assembly of this protein into various geometrical cages. Here, we have extended this approach by appending a coiled coil designed to trimerize in response to binding divalent transition metal ions and thereby achieve metal ion‐dependent assembly of a tetrahedral protein cage. Ni2+, Co2+, Cu2+, and Zn2+ ions were evaluated, with Ni2+ proving the most effective at mediating protein assembly. Characterization of the assembled protein indicated that the metal ion–protein complex formed discrete globular structures of the diameter expected for a complex containing 12 copies of the protein monomer. Protein assembly could be reversed by removing metal ions with ethylenediaminetetraacetic acid or under mildly acidic conditions.

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Rational Engineering of a Designed Protein Cage for siRNA Delivery

Cited by 96 publications

References 56 publications

Two-tier supramolecular encapsulation of small molecules in a protein cage

Two-tier supramolecular encapsulation of small molecules in a protein cage

Multi‐Component Self‐Assembly of Proteins and Inorganic Particles: From Discrete Structures to Biomimetic Materials

Metal‐dependent assembly of a protein nano‐cage

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