RNA Oncological Therapeutics: Intracellular Hairpin RNA Assembly Enables MicroRNA-Triggered Anticancer Functionality

Area of Science:

• Biochemistry
• Molecular Biology
• RNA Therapeutics

Background:

• RNA therapeutics offer versatile targeting of biomolecules.
• Long double-stranded RNA (dsRNA) shows potential as an immune-activating antitumor agent.
• Current dsRNA therapies face challenges in cancer selectivity and cell penetration.

Purpose of the Study:

• To design and synthesize a novel oncolytic RNA hairpin pair (oHP).
• To achieve selective cytotoxicity towards cancer cells expressing microRNA-21 (miR-21).
• To develop a build-up type anticancer agent triggered by oncogenic miRNA.

Main Methods:

• Design and synthesis of a thermodynamically metastable oncolytic RNA hairpin pair (oHP).
• Demonstration of catalytic opening of oHP triggered by miR-21 to form long nicked dsRNA.
• In vitro and in vivo testing of oHP in cancer cells and tumor-bearing mice.

Main Results:

• The oHP was selectively cytotoxic to cancer cells with high miR-21 expression.
• miR-21 triggered the oHP to open, generating a long nicked dsRNA.
• oHP acted as a cytotoxic amplifier in the presence of miR-21 in various cancer models.

Conclusions:

• This study introduces the first build-up type anticancer agent using short RNA molecules triggered by oncogenic miRNA.
• The oHP demonstrates selective cancer cell killing and potential as an RNA therapeutic.
• This approach overcomes limitations of traditional dsRNA antitumor agents.