A boronic acid–rich dendrimer with robust and unprecedented efficiency for cytosolic protein delivery and CRISPR-Cas9 gene editing

Liu, Chongyi; Wan, Tao; Wang, Hui; Song, Zhaobin; Yuan, Ping; Cheng, Yiyun

doi:10.1126/sciadv.aaw8922

Cited by 316 publications

(235 citation statements)

References 43 publications

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“…3a, b). Boronic acid-rich polymers were reported to circumvent multiple intracellular barriers existing during gene and protein delivery [39,44,[49][50][51][52]. The internalized BDP/peptide complexes showed efficient endosomal escape after 4 h incubation with the cells (Fig.…”

Section: Resultsmentioning

confidence: 96%

“…Here, we developed a boronic acid-rich cationic dendrimer for efficient internalization of peptides into different cell lines. Boronic acid is an electron deficient group which could interact with the electron-rich residues on the peptides such as amine and hydroxyl groups via coordination bonding between Lewis acid and base [39][40][41][42][43]. In addition, the cationic dendrimer could bind with anionic groups of cargo peptides via ionic interactions.…”

Section: Introductionmentioning

confidence: 99%

“…The combination of these interacting forces facilitates the binding of cargo peptides to the designed material for intracellular peptide delivery. Besides peptide binding, boronic acid-rich materials were reported to successfully circumvent numerous extracellular and intracellular barriers existing in intracellular delivery of biomacromolecules, such as cell targeting, cellular uptake, endosomal escape and cytosolic cargo release [39,[44][45][46][47][48]. Based on these rationales, the designed boronic acid-rich dendrimer was expected to have high intracellular translocation efficiency towards peptides with various polarities and isoelectric points (pIs).…”

Section: Introductionmentioning

confidence: 99%

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Boronic acid-rich dendrimer for efficient intracellular peptide delivery

Liu

et al. 2019

Sci. China Mater.

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Interests in intracellular peptide delivery have continued to grow, significantly fueled by the importance of peptides and their mimetics in modern cell biology and pharmaceutical industry. However, efficient intracellular delivery of membrane-impermeable peptides of different polarities remains a challenging task. In this study, we develop a general and robust strategy for intracellular peptide delivery by using a boronic acid-rich dendrimer. The designed material is capable of transporting peptides with different polarities and charge properties into the cytosol of various cell lines without inducing additional cytotoxicity. The transduction efficacy and proteolytic stability of cargo peptides delivered by the boronic acid-rich dendrimer are much superior to peptides conjugated with cell penetrant peptides such as octaarginine. In addition, the bioactivities of pro-apoptotic peptides are maintained after intracellular delivery. This study provides a versatile and robust platform for the intracellular delivery of membrane-impermeable peptides.

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Section: Resultsmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Boronic acid-rich dendrimer for efficient intracellular peptide delivery

Liu

et al. 2019

Sci. China Mater.

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“…By the rational design of a chemical structure, polymeric carriers can bypass the issues of serum instability in contrast to lipid carriers . As non‐viral vectors, polymers have been studied intensively for delivering CRISPR/Cas9 elements, largely as a result of their biocompatibility, flexibility, and simplicity, etc …”

Section: Non‐viral Vectors Of Crispr‐cas9mentioning

confidence: 99%

Delivery of CRISPR/Cas9 for therapeutic genome editing

Wan

Xin

et al. 2019

The Journal of Gene Medicine

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107

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The clustered, regularly‐interspaced, short palindromic repeat (CRISPR)‐associated nuclease 9 (CRISPR/Cas9) is emerging as a promising genome‐editing tool for treating diseases in a precise way, and has been applied to a wide range of research in the areas of biology, genetics, and medicine. Delivery of therapeutic genome‐editing agents provides a promising platform for the treatment of genetic disorders. Although viral vectors are widely used to deliver CRISPR/Cas9 elements with high efficiency, they suffer from several drawbacks, such as mutagenesis, immunogenicity, and off‐target effects. Recently, non‐viral vectors have emerged as another class of delivery carriers in terms of their safety, simplicity, and flexibility. In this review, we discuss the modes of CRISPR/Cas9 delivery, the barriers to the delivery process and the application of CRISPR/Cas9 system for the treatment of genetic disorders. We also highlight several representative types of non‐viral vectors, including polymers, liposomes, cell‐penetrating peptides, and other synthetic vectors, for the therapeutic delivery of CRISPR/Cas9 system. The applications of CRISPR/Cas9 in treating genetic disorders mediated by the non‐viral vectors are also discussed.

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“…Importantly, the application of toxin-based nanoparticles, immunotoxins or generically, protein-based drug vehicles [33,34], would largely benefit from potent endosomolytic agents. This is because lysosomal degradation is a critical bottleneck in the delivery route [35], and in this context, many strategies and active materials are currently developed to enhance the necessary cytosolic delivery [36][37][38][39][40]. On the other side, proteins are becoming increasingly valuable biopharmaceuticals [34,[41][42][43], and H6-based functionalization by gene fusion is a common procedure [44].…”

Section: Introductionmentioning

confidence: 99%

Endosomal escape of protein nanoparticles engineered through humanized histidine-rich peptides

et al. 2019

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Poly-histidine peptides such as H6 (HHHHHH) are used in protein biotechnologies as purification tags, protein-assembling agents and endosomal-escape entities. The pleiotropic properties of such peptides make them appealing to design protein-based smart materials or nanoparticles for imaging or drug delivery to be produced in form of recombinant proteins. However, the clinical applicability of H6tagged proteins is restricted by the potential immunogenicity of these segments. In this study, we have explored several humanized histidine-rich peptides in tumor-targeted modular proteins, which can specifically bind and be internalized by the target cells through the tumoral marker CXCR4. We were particularly interested in exploring how protein purification, self-assembling and endosomal escape perform in proteins containing the variant histidine-rich tags. Among the tested candidates, the peptide H5E (HEHEHEHEH) is promising as a good promoter of endosomal escape of the associated fulllength protein upon endosomal internalization. The numerical modelling of cell penetration and endosomal escape of the tested proteins has revealed a negative relationship between the amount of protein internalized into target cells and the efficiency of cytoplasmic release. This fact demonstrates that the His-mediated, proton sponge-based endosomal escape saturates at moderate amounts of internalized protein, a fact that might be critical for the design of protein materials for cytosolic molecular delivery.

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A boronic acid–rich dendrimer with robust and unprecedented efficiency for cytosolic protein delivery and CRISPR-Cas9 gene editing

Cited by 316 publications

References 43 publications

Boronic acid-rich dendrimer for efficient intracellular peptide delivery

Boronic acid-rich dendrimer for efficient intracellular peptide delivery

Delivery of CRISPR/Cas9 for therapeutic genome editing

Endosomal escape of protein nanoparticles engineered through humanized histidine-rich peptides

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