# Novel bioengineered microRNA therapeutics for lung cancer

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $360,586

## Abstract

Lung cancer remains a leading cause of cancer death in both women and men in the United States. There is
a clear need for developing new and more effective therapeutics for the treatment of lung cancer, especially
the most common subtype non-small cell lung cancer (NSCLC). As master regulators of transcriptome and
proteome dynamics, microRNAs (miRNAs or miRs) govern many critical cancer cellular processes including
proliferation, invasion and stemness. Therefore, restoration of tumor suppressive miRNAs (e.g., miR-34a
and miR-124) lost in NSCLC cells represents a new therapeutic strategy. However, current miRNA mimics
for research and development are made by chemical synthesis and decorated with various and extensive
artificial modifications. This is in sharp contrast to miRNA molecules produced in living cells that do not
carry any modifications or just a few necessary posttranscriptional modifications. Indeed it has been well
documented that chemically-engineered/synthesized oligoribonucleotides (e.g., miRNA mimics) are readily
recognized as foreign RNA molecules and thus cause immunogenicity. To break this barrier, we have
made large efforts to develop novel approach for large-scale production of biologic miRNA agents
(BERAs) in living cells. Our identification of hybrid tRNA/pre-miRNA molecules stably expressed in E. coli
opens up a new avenue for RNA bioengineering. Furthermore, we have demonstrated that target miRNAs
(e.g., miR-34a) are selectively released from BERA “prodrugs” in human cells, and consequently regulate
target gene expression, inhibit NSCLC cell proliferation, and suppress xenograft tumor growth while they do
not induce severe immune responses. In addition, our studies have found that liposome-polyethylenimine
(LPP) nanocomplex increases BERA stability in serum and improves delivery efficiency to lung tissues.
Given these exciting preliminary findings, we hypothesize that BERAs can be engineered at higher levels
and on large scale; and fully-humanized BERA/miR-34a and BERA/miR-124 may be delivered by LPP as
novel therapeutics for the treatment of NSCLC. To test the hypothesis, we proposed to establish more stable
ncRNA carriers and produce a set of full-humanized ready-to-use BERAs (Aim 1), delineate the molecular
pharmacological actions of BERAs in the control of human NSCLC cellular processes critical for therapeutic
outcomes (Aim 2), and define the effectiveness and safety profiles of LPP-loaded BERA/miR-34a and
miR-124 in metastatic NSCLC xenograft and patient-derived xenograft (PDX) mouse models (Aim 3). The
proposed research will establish a novel technology for the production of fully-humanized biologic miRNA
agents and open up new directions for the development of biologic RNA therapeutics.

## Key facts

- **NIH application ID:** 9830041
- **Project number:** 5R01CA225958-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Aiming Yu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $360,586
- **Award type:** 5
- **Project period:** 2018-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830041

## Citation

> US National Institutes of Health, RePORTER application 9830041, Novel bioengineered microRNA therapeutics for lung cancer (5R01CA225958-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9830041. Licensed CC0.

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