Revolutionizing RNA Delivery with DNA-Based Nanostructures
RNA-based therapies have transformed modern medicine, offering new treatment avenues for diseases such as cancer, genetic disorders, and infections. Unlike traditional drugs, RNA molecules can precisely target gene expression, minimizing side effects and enabling personalized treatments. However, a major challenge in RNA-based therapeutics lies in efficient delivery—RNA molecules are fragile, prone to degradation, and struggle to enter cells effectively.
In their review article “DNA-based Nanostructures for RNA Delivery,” Yuanyuan Wu and colleagues explore how DNA nanotechnology can be used to overcome these hurdles. The paper highlights three major DNA-based delivery platforms:
DNA Origami – Engineered DNA scaffolds for precise, programmable RNA loading and controlled release.
Frame-Guided Assembly (FGA) – A method for stabilizing lipid nanoparticles (LNPs) to enhance RNA protection and minimize toxicity.
DNA Hydrogels – Crosslinked DNA networks designed for sustained, controlled RNA delivery in therapeutic applications.
Challenges in RNA Delivery
RNA-based drugs, including siRNA, miRNA, and mRNA, have enormous therapeutic potential, but their delivery into target cells faces several roadblocks:
Stability – RNA molecules are highly susceptible to degradation by enzymes (ribonucleases) in the bloodstream.
Cellular Barriers – The lipid membrane of cells is difficult for RNA to cross, limiting its uptake.
Immune Response – Many current RNA delivery methods, such as viral vectors, can trigger unwanted immune reactions.
Scientists have attempted to bypass these issues with non-viral vectors, including lipid nanoparticles (LNPs), polymers, and peptides. While LNPs have been widely adopted (notably in mRNA COVID-19 vaccines), they suffer from toxicity, poor storage stability, and immunogenicity.
DNA nanotechnology presents a compelling alternative. DNA molecules are biocompatible, highly programmable, and capable of protecting RNA from degradation, making them a powerful tool for RNA delivery.
DNA Origami for RNA Delivery
DNA origami, pioneered by Paul Rothemund in 2006, takes advantage of Watson–Crick base pairing to fold DNA into precise, self-assembling nanostructures. These structures can serve as RNA carriers, offering:
High stability – Protecting RNA from enzymatic degradation.
Targeted delivery – RNA-loaded nanostructures can be engineered to recognize specific cell types.
Controlled release – RNA can be programmed to release under specific conditions (e.g., low pH in tumors).
Researchers have designed and tested various DNA origami shapes, including:
Tetrahedrons – Compact, rigid structures with high cellular uptake.
Rectangular and tubular structures – Larger carriers capable of holding multiple RNA molecules.
Soccer-ball-shaped frameworks – Mimicking viruses for improved gene transfection.
Recent studies have shown DNA origami can effectively deliver RNA to cells, successfully silencing genes linked to drug resistance and cancer progression. This approach could pave the way for highly specific, low-toxicity RNA therapeutics.
Enhancing Lipid Nanoparticles for RNA Delivery
Lipid nanoparticles (LNPs) revolutionized mRNA-based vaccines, but toxicity, variability in manufacturing, and delivering larger therapeutics and to targets outside the liver remain major challenges. Frame-Guided Assembly (FGA) is a newly developed approach that enhances LNP structure and function by incorporating nucleic acid scaffolds.
How does FGA work?
Instead of relying on electrostatic interactions, which can cause premature RNA release, FGA provides a rigid framework that stabilizes LNPs.
RNA is encapsulated within structured vesicles, reducing immune activation and improving storage stability.
Gold nanoparticles or peptides can be incorporated to further enhance RNA protection and cellular uptake.
Researchers have successfully used FGA-stabilized LNPs to deliver Bcl-2-targeting siRNA, effectively suppressing tumor growth in cancer models. By minimizing immune reactions and maximizing RNA stability, FGA could dramatically improve the safety and effectiveness of RNA therapies.
DNA Hydrogels – A Soft, Sustained-Release System for RNA
DNA hydrogels are three-dimensional, water-absorbing structures formed by crosslinking DNA strands. These materials have unique properties that make them ideal for drug delivery:
Long circulation time – Slowly releasing RNA over time for sustained therapeutic effects.
High biocompatibility – Minimal toxicity or immune response.
Adaptability – Hydrogels can be tuned to release RNA in response to specific biological triggers.
Researchers have designed stimuli-responsive DNA hydrogels that release RNA when exposed to:
Low pH (e.g., tumor environments)
Enzymes like RNase H (which selectively degrades hybridized RNA)
Specific microRNAs (biomarkers associated with cancer)
For example, tumor-responsive hydrogels have been engineered to deliver RNA selectively to cancer cells, suppressing tumor growth while leaving healthy tissues untouched. This precision delivery system could greatly reduce side effects in cancer therapy.
The Future of DNA Nanotechnology for RNA Therapeutics
DNA-based nanostructures represent a breakthrough in RNA delivery, addressing many of the challenges that have hindered RNA-based medicine. Looking ahead, scientists are exploring:
Hybrid DNA–RNA origami scaffolds for improved RNA encapsulation.
AI-driven nanostructure design to optimize RNA loading and release.
Clinical applications in gene therapy and cancer treatment.
With ongoing research, DNA nanotechnology could revolutionize how RNA drugs are delivered, unlocking new possibilities in personalized medicine, targeted cancer treatments, and regenerative therapies.
By refining design strategies and overcoming delivery barriers, scientists are moving closer to a future where RNA-based therapies are safer, more effective, and widely accessible.
References:
1. Wu, Y., Luo, L., Hao, Z., & Liu, D. (2024). DNA-based nanostructures for RNA delivery. Medical review (2021), 4(3), 207–224.