Engineering acyclovir-induced RNA nanodevices for reversible and tunable control of aptamer function

Area of Science:

• Biochemistry
• Molecular Biology
• Nanotechnology

Background:

• Small molecule-regulated RNA devices offer cellular function modulation but often have toxicities.
• Existing methods for controlling RNA devices are limited by toxicity and lack of precise control.

Purpose of the Study:

• To develop a novel method for creating drug-regulated RNA nanodevices (RNs) using acyclovir.
• To engineer acyclovir-regulated RNs for temporal, tunable, and reversible control of intracellular aptamers.
• To establish a platform for transforming aptamers into acyclovir-controllable antagonists against physiologic target proteins.

Main Methods:

• A modular approach using a scaffold with a central F30 three-way junction.
• Integration of an acyclovir aptamer on the input arm and a variable effector-binding aptamer on the output arm.
• Demonstration of control over the Broccoli aptamer and the iron-responsive element (IRE) using acyclovir.

Main Results:

• Successfully created acyclovir-regulated RNA nanodevices (RNs) with minimal toxicity.
• Achieved temporal, tunable, and reversible control of intracellular aptamers.
• Demonstrated precise control over iron-regulatory protein (IRP) sequestration via IRE regulation, inhibiting ferroptosis.

Conclusions:

• The described method provides a versatile platform for engineering acyclovir-controllable RNA nanodevices.
• This approach overcomes toxicity limitations of previous small molecules used in RNA devices.
• The developed RNs offer a promising strategy for developing targeted therapies against various physiological targets.