# Making Oligonucleotides Better Biopharmaceuticals by Steric Protection

> **NIH NIH R01** · NORTHEASTERN UNIVERSITY · 2021 · $311,457

## Abstract

Project Summary/Abstract
Significant interests exist for using oligonucleotides as therapeutic agents, which face several
biopharmaceutical difficulties, including stability and delivery issues, and sequence- and/or chemical
structure-specific, non-hybridization activities, such as coagulopathies and stimulation of the immune
system. These difficulties have been in part overcome by chemical modification of the oligonucleotide
backbone or by using delivery systems (oftentimes polycationic structures), which enhance nuclease
stability and improve delivery efficiency. However, these approaches either give rise to new challenges
(e.g. toxicity and immunogenicity), or cannot adequately address all of the negative aspects. Therefore, a
system that can improve nuclease stability, preserve target-binding capability, minimize all off-target
effects, and improve biodistribution is still very much sought after. Our preliminary studies have
demonstrated that “compaction” of DNA can be achieved by inserting it into a high-density brush polymer
environment, which enables the DNA to bind selectively to a complementary DNA strand, while access
by various proteins is limited. The binding of DNA with proteins such as nucleases, toll-like receptor 9,
and thrombin is generally the first step to non-hybridization side effects. Therefore, the brush polymer-
DNA conjugates should bypass many of the side effects of oligonucleotides and has the potential to be
applied to essentially all forms of oligonucleotides, i.e. antisense DNA, siRNA, microRNA, aptamers,
ribozymes, etc., to improve their biopharmaceutical characteristics. The outcome of this study would be a
new class of biocompatible and non-immunostimulatory oligonucleotide-based gene therapy agents, and
a fundamental understanding of how its molecular parameters can impact its in vivo and in vitro
properties.

## Key facts

- **NIH application ID:** 10259829
- **Project number:** 5R01GM121612-05
- **Recipient organization:** NORTHEASTERN UNIVERSITY
- **Principal Investigator:** Ke Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $311,457
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10259829

## Citation

> US National Institutes of Health, RePORTER application 10259829, Making Oligonucleotides Better Biopharmaceuticals by Steric Protection (5R01GM121612-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10259829. Licensed CC0.

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