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Peer-reviewedCC BY 4.0ACS Central Science

Ribonuclease H1 Hijacking: Oncotherapeutics through MicroRNA-Triggered Intracellular Construction of Long DNA/RNA Heteroduplexes

  • Kunihiko Morihiro1
  • Naoki Harada1
  • Shuichiro Koga1
  • Yunsong Xu1
  • Tamako Aiba1
  • Akimitsu Okamoto1
  1. 1The University of Tokyo , , , ,
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Abstract

Ribonuclease H1 (RNase H1) cleaves the RNA strand of DNA/RNA heteroduplexes and plays essential roles in R-loop resolution, mitochondrial DNA replication, and antisense oligonucleotide (ASO) activity. Because RNase H1 has also been implicated in ASO-induced cytotoxicity, considerable effort has been focused on minimizing its activation. Here we present a reverse strategy that harnesses RNase H1-mediated cytotoxicity for cancer therapy using an oncogenic microRNA (miR-21) as an intracellular trigger. A designed hairpin DNA/hairpin RNA pair undergoes a hybridization chain reaction to assemble long-nicked DNA/RNA heteroduplexes selectively in miR-21-overexpressing cells. The resulting heteroduplexes induce RNase H1-dependent cytotoxicity in cancer cells while exhibiting minimal effects on normal cells. Treatment also caused redistribution of the paraspeckle protein P54nrb from the nucleoplasm to the nucleoli, consistent with RNase-H1-associated nucleolar stress. Furthermore, lipid-nanoparticle-mediated delivery of the DNA/RNA heterohairpin pair significantly suppressed tumor growth in mice. These findings establish a therapeutic strategy that converts RNase H1, traditionally regarded as a source of oligonucleotide toxicity, into a mechanism for selective anticancer activity through the intracellular assembly of long DNA/RNA heteroduplexes.

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Cite

BibTeXRIS
BibTeX
@article{morihiro2026ribonuclease,
  title = {{Ribonuclease H1 Hijacking: Oncotherapeutics through MicroRNA-Triggered Intracellular Construction of Long DNA/RNA Heteroduplexes}},
  author = {Kunihiko Morihiro and Naoki Harada and Shuichiro Koga and Yunsong Xu and Tamako Aiba and Akimitsu Okamoto},
  journal = {ACS Central Science},
  year = {2026},
  month = oct,
  doi = {10.1021/acscentsci.6c01046},
  url = {https://pubs.acs.org/acscii/article/doi/10.1021/acscentsci.6c01046/5449244/Ribonuclease-H1-Hijacking-Oncotherapeutics-through},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Ribonuclease H1 Hijacking: Oncotherapeutics through MicroRNA-Triggered Intracellular Construction of Long DNA/RNA Heteroduplexes
AU  - Kunihiko Morihiro
AU  - Naoki Harada
AU  - Shuichiro Koga
AU  - Yunsong Xu
AU  - Tamako Aiba
AU  - Akimitsu Okamoto
PY  - 2026
DA  - 2026/10/12
JO  - ACS Central Science
DO  - 10.1021/acscentsci.6c01046
UR  - https://pubs.acs.org/acscii/article/doi/10.1021/acscentsci.6c01046/5449244/Ribonuclease-H1-Hijacking-Oncotherapeutics-through
AB  - Ribonuclease H1 (RNase H1) cleaves the RNA strand of DNA/RNA heteroduplexes and plays essential roles in R-loop resolution, mitochondrial DNA replication, and antisense oligonucleotide (ASO) activity. Because RNase H1 has also been implicated in ASO-induced cytotoxicity, considerable effort has been focused on minimizing its activation. Here we present a reverse strategy that harnesses RNase H1-mediated cytotoxicity for cancer therapy using an oncogenic microRNA (miR-21) as an intracellular trigger. A designed hairpin DNA/hairpin RNA pair undergoes a hybridization chain reaction to assemble long-nicked DNA/RNA heteroduplexes selectively in miR-21-overexpressing cells. The resulting heteroduplexes induce RNase H1-dependent cytotoxicity in cancer cells while exhibiting minimal effects on normal cells. Treatment also caused redistribution of the paraspeckle protein P54nrb from the nucleoplasm to the nucleoli, consistent with RNase-H1-associated nucleolar stress. Furthermore, lipid-nanoparticle-mediated delivery of the DNA/RNA heterohairpin pair significantly suppressed tumor growth in mice. These findings establish a therapeutic strategy that converts RNase H1, traditionally regarded as a source of oligonucleotide toxicity, into a mechanism for selective anticancer activity through the intracellular assembly of long DNA/RNA heteroduplexes.
SN  - 2374-7943
SN  - 2374-7951
ER  -