# Making Oligonucleotides Better Biopharmaceuticals by Steric Protection

> **NIH NIH R01** · NORTHEASTERN UNIVERSITY · 2024 · $88,145

## Abstract

Project Summary/Abstract
Oligonucleotides face several biopharmaceutical difficulties, including stability and delivery issues as well
as non-hybridization activities such as coagulopathy and unwanted activation of the immune system. We
have developed a unique oligonucleotide delivery system, termed pacDNA, which uses a high-density
bottlebrush polymer to provide oligonucleotides with binding selectivity. The polymer amounts to an
entropic barrier, reducing access to the oligonucleotide by various proteins (and thus side effects) but still
allows for unhindered hybridization. This novel strategy not only improves nuclease stability, preserves
target-binding capability, and minimizes off-target side effects, but also massively enhances plasma
pharmacokinetics, tissue retention, and antisense potency in vivo. Our current studies also reveal that the
pacDNA’s pharmacological properties are intimately related to the bottlebrush backbone. In addition, the
pacDNA appears to be uniquely capable of evading anti-carrier adaptive immunity, which is useful for
therapies that requires long-term/frequent dosing. Finally, the pacDNA deposits into tissues and organs
that lack mature delivery technologies for, such as the skin, the skeletal muscle, and the heart. These
surprising and enabling discoveries will be the basis for investigations in the next funding period, in which
we will 1) explore the property space of the pacDNA structure using a combinatorial polymer library with
specific backbone compositions and monomer sequences, and 2) probe in vivo properties of the pacDNA
in mice. We anticipate that accomplishment of these objectives will yield significant fundamental
understanding of this class of materials and bring us much closer to clinical evaluation of pacDNA.

## Key facts

- **NIH application ID:** 11056394
- **Project number:** 3R01GM121612-07S1
- **Recipient organization:** NORTHEASTERN UNIVERSITY
- **Principal Investigator:** Ke Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $88,145
- **Award type:** 3
- **Project period:** 2017-09-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11056394

## Citation

> US National Institutes of Health, RePORTER application 11056394, Making Oligonucleotides Better Biopharmaceuticals by Steric Protection (3R01GM121612-07S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11056394. Licensed CC0.

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