# A New Class of Chemically Modified Small RNA Inhibitors against Fusobacterium nucleatum

> **NIH NIH R03** · NORTHEASTERN UNIVERSITY · 2022 · $173,830

## Abstract

Oral microbiome represents an exciting frontier in medicine, and early successes in the field have demonstrated
the dynamic interactions among individual microbial species and highlighted the crosstalk between oral
microbiota and their hosts at the mucosal interface. While the oral microbiome field has made impressive strides
toward these goals, much of our knowledge is typically inferred from correlation studies between bacterial
compositions and disease progression. However, there is an immediate need for targeted modulators to prove
a causal relationship by selectively eliminating individual species in a multispecies community in a manner
analogous to genetic tools that identify links between genotype and phenotype via targeted knockouts. The
present R03 application will build on a recent fundamental study by our collaborators, which uncovered crosstalk
between Fusobacterium nucleatum (Fn) and transfer RNA-derived small RNAs (tsRNAs) derived from human
saliva and oral epithelial cells. Fn is a key oral commensal and opportunistic periodontal pathogen, and has
garnered much attention due to its implications in periodontal diseases, preterm birth, and colon cancer. However,
no tool exists that can selectively eliminate Fn to understand its role in complex diseases. In parallel, tsRNA
represents a new class of small RNAs that can modulate gene expression in prokaryotes and eukaryotes, and
recent work has demonstrated that host cells may employ certain tsRNAs to target Fn. Specifically, immortalized
human oral epithelial cells can release tsRNA-000794 and tsRNA-020498 in response to Fn infection. Intriguingly,
synthetic mimics of tsRNA-000794 and tsRNA-020498, but not scrambled RNA sequences, can kill Fn in
planktonic culture, but not Porphyromonas ginigivalis, a gram-negative periodontal pathogen, or Streptococcus
mitis, a health-associated gram-positive oral bacterium. However, micromolar concentrations are needed to
achieve inhibition against different Fn strains, which poses a challenge for potential applications. To address this
limitation, the PI has leveraged his background in RNA chemistry and delivery to chemically modify terminal
nucleotides at the 5’ and 3’ ends of the two tsRNAs (MOD-tsRNAs). Impressively, this invention resulted in
~1000-fold reductions in the concentrations of MOD-tsRNA-000794 and MOD-tsRNA-020498 to achieve
equivalent potency and specificity against Fn compared to natural counterparts. Motivated by the preliminary
data, we will perform two independent and complementary aims towards this new class of MOD-tsRNA inhibitors.
Specifically, we will demonstrate the efficacy and specificity of MOD-tsRNAs against Fn using relevant in vitro
biofilm and multispecies models (Aim 1). In parallel, we will identify the targets of MOD-tsRNAs in Fn (Aim 2).
While this application focuses on two specific tsRNAs and one oral microbe, the conceptual framework will pave
the way for a new class of host-derived small RNA inhibitors toward...

## Key facts

- **NIH application ID:** 10353249
- **Project number:** 1R03DE031329-01
- **Recipient organization:** NORTHEASTERN UNIVERSITY
- **Principal Investigator:** Jiahe Li
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $173,830
- **Award type:** 1
- **Project period:** 2022-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10353249

## Citation

> US National Institutes of Health, RePORTER application 10353249, A New Class of Chemically Modified Small RNA Inhibitors against Fusobacterium nucleatum (1R03DE031329-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10353249. Licensed CC0.

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