Programmable RNA loading of extracellular vesicles with toehold-release purification

The quest for safe, efficient, and biocompatible drug delivery carriers has long been a challenge. Synthetic nanoparticles, while widely used, come with their drawbacks, including low biocompatibility and triggering immune responses. However, a natural alternative has emerged: extracellular vesicles (EVs), tiny vesicles secreted by cells that offer native, safe, and multifunctional delivery vessels. Despite their promise, loading EVs with large biomolecules like messenger RNA (mRNA) has remained a formidable hurdle—until now.

A groundbreaking study has unveiled a controlled loading methodology that bridges the gap between EVs and mRNA-loaded liposomes, called fused EV–liposome particles (EVLs). Led by innovative researchers at Aarhus University, this approach harnesses DNA-mediated and programmed fusion to seamlessly merge EVs with mRNA-loaded liposomes. The fusion process, meticulously characterized at the single-particle level using real-time microscopy, allows for precise monitoring of EV surface immobilization via lipidated biotin-DNA handles.

The beauty of this methodology lies in its scalability and efficiency. By employing a DNA strand-replacement reaction, fused EVL particles can be easily collected, paving the way for mass production on a scale never before achieved. Transferring the fusion reaction to magnetic beads further amplifies production, enabling a staggering one million-fold increase in EVL production.

But the true test lies in its application. In a remarkable demonstration, the researchers successfully encapsulated mCherry mRNA—a fluorescent protein-encoding mRNA—within EVLs and tested their efficacy in HEK293-H cells. The results were striking: EVLs exhibited enhanced transfection and translation compared to conventional liposomes or lipid nanoparticles (LNPs), showcasing their potential as a powerful tool for RNA therapeutics delivery.

The implications of this breakthrough are profound. With EVLs poised to revolutionize the field of RNA therapeutics delivery, the door is opened to a new era of precision medicine and targeted treatments for a myriad of diseases. From cancer to genetic disorders, the ability to harness nature’s own nanocarriers offers hope for safer, more effective therapies with fewer side effects.

Malle MG, Song P, Löffler PMG, Kalisi N, Yan Y, Valero J, Vogel S, Kjems J. (2024) Programmable RNA Loading of Extracellular Vesicles with Toehold-Release Purification. J Am Chem Soc [Epub ahead of print]. [article]

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