# Computation-aided Molecular Design of DNA-Inspired Janus Base Biomaterials for Intracellular Delivery

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT STORRS · 2024 · $424,451

## Abstract

Abstract
 The overall goal of this proposal is to develop novel biomaterials for intracellular therapeutics delivery.
While messenger RNAs (mRNAs) are recognized as promising candidates for RNA therapeutics (such as anti-
inflammatory drugs) as well as research tools (such as delivering Cas9 mRNA for gene editing), unlike many
chemical molecules or antibody proteins, mRNAs need to be delivered into cell cytoplasm to be functional.
Various types of materials have been developed for successful intracellular delivery of small RNAs, but it is still
a major challenge to achieve effective delivery of mRNAs at both cellular and systemic levels. We aim to
overcome this by optimizing the biointerface properties of DNA-inspired Janus base biomaterials using
computational methods for molecular design, with experimental validation.
 There are two important obstacles for effective mRNA delivery: at the cellular level, the delivered RNA
cargos can be trapped and degraded inside cell endosomes after endocytosis (internalization by cells). For
example, lipid nanoparticles (LNPs) are commonly used delivery vehicles for mRNA in both academic and
industrial settings. However, the effectiveness of conventional LNPs is limited by their poor endosomal escape
ability which leads to the destruction of a significant portion of RNA cargos. At the systemic level (when
administrated intravenously), RNA delivery materials usually require surface modifications to reduce specific
and non-specific binding of serum proteins (or formation of protein coronas), increase blood circulation time,
and improve biodistribution. Polyethylene glycol (PEG) is a widely used surface modification polymer in clinics,
but its efficacy is significantly restricted because it can cause undesired immunogenicity in patients.
 To overcome these limitations, we will develop a novel delivery technology by manipulating the biointerface
properties of the DNA-inspired Janus base nanopieces (JBNps). JBNps are slimmer than conventional
spherical particles, allowing for enhanced infiltration into tissue matrices and barriers. As a result, JBNps have
a distinct advantage for delivery into “hard-to-penetrate” tissues such as articular cartilage and kidneys. Our
central hypothesis of this study is that sidechain and zwitterionic modifications can manipulate biointerface
properties of JBNps, accomplishing highly effective mRNA delivery into target tissues. Once our hypothesis is
confirmed, we can use JBNps to deliver mRNA for articular cartilage and kidney applications such as anti-
inflammatory mRNA therapeutics.

## Key facts

- **NIH application ID:** 10999709
- **Project number:** 1R01GM155969-01
- **Recipient organization:** UNIVERSITY OF CONNECTICUT STORRS
- **Principal Investigator:** Yupeng Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $424,451
- **Award type:** 1
- **Project period:** 2024-09-15 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999709

## Citation

> US National Institutes of Health, RePORTER application 10999709, Computation-aided Molecular Design of DNA-Inspired Janus Base Biomaterials for Intracellular Delivery (1R01GM155969-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10999709. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*