Phenylboronic Acid-Functionalized Polyplexes Tailored to Oral CRISPR Delivery

Naoto Yoshinaga; Joyce K. Zhou; Cong Xu; Chai Hoon Quek; Yuefei Zhu; Ding Tang; Lin Yung Hung; Sarah A. Najjar; Chin Ying Angela Shiu; Kara Gross Margolis; Yeh Hsing Lao; Kam W. Leong

doi:10.1021/acs.nanolett.2c02306

Phenylboronic Acid-Functionalized Polyplexes Tailored to Oral CRISPR Delivery

Naoto Yoshinaga, Joyce K. Zhou, Cong Xu, Chai Hoon Quek, Yuefei Zhu, Ding Tang, Lin Yung Hung, Sarah A. Najjar, Chin Ying Angela Shiu, Kara Gross Margolis, Yeh Hsing Lao, Kam W. Leong

Molecular Pathobiology

Research output: Contribution to journal › Article › peer-review

Abstract

Effective delivery of the CRISPR-Cas9 components is crucial to realizing the therapeutic potential. Although many delivery approaches have been developed for this application, oral delivery has not been explored due to the degradative nature of the gastrointestinal tract. For this issue, we developed a series of novel phenylboronic acid (PBA)-functionalized chitosan-polyethylenimine (CS-PEI) polymers for oral CRISPR delivery. PBA functionalization equipped the polyplex with higher stability, smooth transport across the mucus, and efficient endosomal escape and cytosolic unpackaging in the cells. From a library of 12 PBA-functionalized CS-PEI polyplexes, we identified a formulation that showed the most effective penetration in the intestinal mucosa after oral gavage to mice. The optimized formulation performed feasible CRISPR-mediated downregulation of the target protein and reduction in the downstream cholesterol. As the first oral CRISPR carrier, this study suggests the potential of addressing the needs of both local and systemic editing in a patient-compliant manner.

Original language	English (US)
Pages (from-to)	757-764
Number of pages	8
Journal	Nano Letters
Volume	23
Issue number	3
DOIs	https://doi.org/10.1021/acs.nanolett.2c02306
State	Published - Feb 8 2023

Keywords

CRISPR-Cas9
Chitosan
Genome editing
Oral gene delivery
Phenylboronic acid

ASJC Scopus subject areas

Bioengineering
General Chemistry
General Materials Science
Condensed Matter Physics
Mechanical Engineering

Access to Document

10.1021/acs.nanolett.2c02306

Cite this

@article{c1ae7dbfe6854ca7bd8d769feee680f5,

title = "Phenylboronic Acid-Functionalized Polyplexes Tailored to Oral CRISPR Delivery",

abstract = "Effective delivery of the CRISPR-Cas9 components is crucial to realizing the therapeutic potential. Although many delivery approaches have been developed for this application, oral delivery has not been explored due to the degradative nature of the gastrointestinal tract. For this issue, we developed a series of novel phenylboronic acid (PBA)-functionalized chitosan-polyethylenimine (CS-PEI) polymers for oral CRISPR delivery. PBA functionalization equipped the polyplex with higher stability, smooth transport across the mucus, and efficient endosomal escape and cytosolic unpackaging in the cells. From a library of 12 PBA-functionalized CS-PEI polyplexes, we identified a formulation that showed the most effective penetration in the intestinal mucosa after oral gavage to mice. The optimized formulation performed feasible CRISPR-mediated downregulation of the target protein and reduction in the downstream cholesterol. As the first oral CRISPR carrier, this study suggests the potential of addressing the needs of both local and systemic editing in a patient-compliant manner.",

keywords = "CRISPR-Cas9, Chitosan, Genome editing, Oral gene delivery, Phenylboronic acid",

author = "Naoto Yoshinaga and Zhou, {Joyce K.} and Cong Xu and Quek, {Chai Hoon} and Yuefei Zhu and Ding Tang and Hung, {Lin Yung} and Najjar, {Sarah A.} and Shiu, {Chin Ying Angela} and Margolis, {Kara Gross} and Lao, {Yeh Hsing} and Leong, {Kam W.}",

note = "Publisher Copyright: {\textcopyright} 2023 American Chemical Society.",

year = "2023",

month = feb,

day = "8",

doi = "10.1021/acs.nanolett.2c02306",

language = "English (US)",

volume = "23",

pages = "757--764",

journal = "Nano Letters",

issn = "1530-6984",

publisher = "American Chemical Society",

number = "3",

}

TY - JOUR

T1 - Phenylboronic Acid-Functionalized Polyplexes Tailored to Oral CRISPR Delivery

AU - Yoshinaga, Naoto

AU - Zhou, Joyce K.

AU - Xu, Cong

AU - Quek, Chai Hoon

AU - Zhu, Yuefei

AU - Tang, Ding

AU - Hung, Lin Yung

AU - Najjar, Sarah A.

AU - Shiu, Chin Ying Angela

AU - Margolis, Kara Gross

AU - Lao, Yeh Hsing

AU - Leong, Kam W.

PY - 2023/2/8

Y1 - 2023/2/8

N2 - Effective delivery of the CRISPR-Cas9 components is crucial to realizing the therapeutic potential. Although many delivery approaches have been developed for this application, oral delivery has not been explored due to the degradative nature of the gastrointestinal tract. For this issue, we developed a series of novel phenylboronic acid (PBA)-functionalized chitosan-polyethylenimine (CS-PEI) polymers for oral CRISPR delivery. PBA functionalization equipped the polyplex with higher stability, smooth transport across the mucus, and efficient endosomal escape and cytosolic unpackaging in the cells. From a library of 12 PBA-functionalized CS-PEI polyplexes, we identified a formulation that showed the most effective penetration in the intestinal mucosa after oral gavage to mice. The optimized formulation performed feasible CRISPR-mediated downregulation of the target protein and reduction in the downstream cholesterol. As the first oral CRISPR carrier, this study suggests the potential of addressing the needs of both local and systemic editing in a patient-compliant manner.

AB - Effective delivery of the CRISPR-Cas9 components is crucial to realizing the therapeutic potential. Although many delivery approaches have been developed for this application, oral delivery has not been explored due to the degradative nature of the gastrointestinal tract. For this issue, we developed a series of novel phenylboronic acid (PBA)-functionalized chitosan-polyethylenimine (CS-PEI) polymers for oral CRISPR delivery. PBA functionalization equipped the polyplex with higher stability, smooth transport across the mucus, and efficient endosomal escape and cytosolic unpackaging in the cells. From a library of 12 PBA-functionalized CS-PEI polyplexes, we identified a formulation that showed the most effective penetration in the intestinal mucosa after oral gavage to mice. The optimized formulation performed feasible CRISPR-mediated downregulation of the target protein and reduction in the downstream cholesterol. As the first oral CRISPR carrier, this study suggests the potential of addressing the needs of both local and systemic editing in a patient-compliant manner.

KW - CRISPR-Cas9

KW - Chitosan

KW - Genome editing

KW - Oral gene delivery

KW - Phenylboronic acid

UR - http://www.scopus.com/inward/record.url?scp=85146578427&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85146578427&partnerID=8YFLogxK

U2 - 10.1021/acs.nanolett.2c02306

DO - 10.1021/acs.nanolett.2c02306

M3 - Article

C2 - 36648291

AN - SCOPUS:85146578427

SN - 1530-6984

VL - 23

SP - 757

EP - 764

JO - Nano Letters

JF - Nano Letters

IS - 3

ER -

Phenylboronic Acid-Functionalized Polyplexes Tailored to Oral CRISPR Delivery

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this