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

Research output: Contribution to journalArticlepeer-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 languageEnglish (US)
Pages (from-to)757-764
Number of pages8
JournalNano Letters
Volume23
Issue number3
DOIs
StatePublished - Feb 8 2023

Keywords

  • CRISPR-Cas9
  • Chitosan
  • Genome editing
  • Oral gene delivery
  • Phenylboronic acid

ASJC Scopus subject areas

  • Bioengineering
  • Chemistry(all)
  • Materials Science(all)
  • Condensed Matter Physics
  • Mechanical Engineering

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