# Cell-specific nanocarrier with endocytic and endosomolytic activities for therapeutic genome editing

> **NIH NIH UG3** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $765,041

## Abstract

Abstract(
!
 Our goal is to develop novel nanoplatforms for efficient in vivo delivery of genome editing
machinery into specific cell types and tissues; nanodelivery systems that are non-toxic and can
be used for therapeutic genome editing in human. Regarding nanocarrier, we will engineer the
innovative hepatitis E viral nanoparticle (HEVNP) developed by the Cheng (one of the PIs)
laboratory, such that cell specific targeting/endocytic ligand will be displayed on the viral
nanoparticle surface, and genome editing machinery and endosomolytic peptides will be
encapsulated inside the core. HEVNP is resistant to gastric acid environment and therefore can
deliver payload to intestine via oral route. We hypothesize that through introduction of stealth
peptide elements and cell-type specific targeting ligand on the viral capsid proteins, such novel
nanocarrier can deliver gene editing machinery to specific cell type, not only via the oral route,
but also via the intravenous route. Our goal is to genome edit intestinal adenomatous polyp cells,
intestinal epithelial cells, and intestinal stem cells of ApcMin/+ mice (a mouse model of familial
adenomatous polyposis) by correcting a mutant Apc tumor suppressor gene, leading to
prevention of new polyp formation and regression of existing polyps (size & number).
 We will employ the enabling one-bead one-compound (OBOC) and one-bead two-compound
(OB2C) combinatorial library methods (invented by Dr. Lam, one of the PIs) to develop D-amino
acid containing targeting/endocytic ligands against intestinal adenomatous polyp cells, intestinal
epithelial cells, and intestinal stem cells of ApcMin/+ mice. We will use the OBOC method to
discover membrane active peptides with endosomolytic activities. These endosomolytic peptides
will bind to endosome at pH5 but not to plasma membrane at pH7.2. Specific aims are as follows:
UG3 (Phase 1)
Aim 1: To design and synthesize OB2C/OBOC combinatorial libraries for the discovery of (a) cell-
specific targeting and endocytic peptides, and (b) endosomolytic peptides.
Aim 2: (a) To engineer hepatitis E viral nanoparticle (HEVNP) with cell-specific targeting ligands,
(b) to design genome editing machinery for GFP, luciferase and Apc correction, and (c) to
assemble a series of nanoconstructs encapsulating the genome machinery and endosomolytic
peptides.
Aim 3: To evaluate the genome editing functions of the nanoconstructs from aim 2, in vitro with
murine intestinal enterocytes and adenomatous polyp cells, and in vivo (oral & iv) with Apcmin/+
mice.
UH3 (Phase 2)
Aim 1, 2 & 3: To scale up the production of the genome editing nanodelivery platform. To perform
preclinical pharmacology/toxicology studies in mouse and Rhesus macaques. To collaborate with
investigator from SCGE Large Animal Testing Centers on validation of the delivery system.
!

## Key facts

- **NIH application ID:** 10001068
- **Project number:** 5UG3TR002866-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** R.Holland Cheng
- **Activity code:** UG3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $765,041
- **Award type:** 5
- **Project period:** 2019-08-22 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001068

## Citation

> US National Institutes of Health, RePORTER application 10001068, Cell-specific nanocarrier with endocytic and endosomolytic activities for therapeutic genome editing (5UG3TR002866-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10001068. Licensed CC0.

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