The Future of RNA Therapeutics, From Design to Delivery
The COVID-19 pandemic catalyzed renewed interest in RNA therapeutics, which hold promise for drugging the undruggable.
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RNA therapeutics have existed since the late 90s but have only come into focus in the last few years. This renewed interest has largely been attributed to the success of messenger RNA (mRNA) vaccines employed during the COVID-19 pandemic. These vaccines helped beat back the virus and showed that mRNA was safe, efficacious and could work at scale.
Following the success of mRNA vaccines, there has been a surge in interest in RNA therapies, which saw a 53% increase in trial initiations in the last quarter of 2024. In contrast to conventional protein-targeting and DNA-based medicines, RNA can theoretically target any gene of interest. This opens the possibility of treating rare conditions and targeting previously “undruggable” proteins. In this article, we will explore the current landscape of RNA therapeutics and discuss some of the innovative technologies designed to realize the full potential of these therapies.
The rise and fall (and rise again) of RNA therapies
RNA therapies first came onto the scene in 1998 with the approval of Vitravene™ (fomivirsen), an antisense oligonucleotide (ASO) indicated for the treatment of cytomegalovirus retinitis – an infection of the retina that can rapidly lead to blindness – in carriers of human immunodeficiency virus (HIV). Despite initial enthusiasm, the drug was eventually withdrawn from the market because of a lack of demand, owing to the success of antiretroviral therapy in reducing the risk of infections in HIV-positive individuals.1
Antisense oligonucleotides (ASOs)
Antisense oligonucleotides are short single-stranded oligonucleotides that bind to complementary RNA sequences. They can alter RNA and reduce, restore or modify protein expression.
20 years after Vitravene’s approval the RNA market remained small, with few new product approvals. It wasn't until 2018 that the first small interfering RNA (siRNA) therapy would enter the market in the form of Onpattro™ (patisiran). This would ultimately be followed by a wave of mRNA therapies in the face of the COVID-19 pandemic, driven by the pioneering work of Dr. Katalin Karikó and Dr. Drew Weissman, who shared the 2023 Nobel Prize in Medicine and Physiology for their research on nucleoside base modifications.
Small interfering RNA (siRNA)
Small interfering RNA are double-stranded RNA molecules most notably involved in the RNA interference (RNAi) pathway where they interfere with gene expression by targeting specific mRNA for degradation.
Catalyzed by the success of mRNA vaccines, interest in RNA therapies has grown significantly with siRNAs, ASOs and mRNAs accounting for a large proportion of the RNA therapeutics pipeline. Research efforts are now focused on maximizing the potential of these biopharmaceuticals.
Drugging the undruggable
It is estimated that only 0.05% of the human genome has been drugged by currently approved small molecule and antibody drugs. In addition, approximately 85% of proteins lack specific clefts and pockets for small molecule binding. Since many proteins have similar structures, it is also not always easy to target a single specific protein.2
RNA therapies are incredibly versatile and can theoretically target any gene of interest. Molecules such as ASOs and siRNA can directly target mRNAs and noncoding RNAs through Watson–Crick base-pairing. As RNA-based drugs can block the biogenesis of specific proteins without altering the genome, they may be better suited to inhibiting their production, improving therapeutic efficacy.
Another key benefit of RNA-based drugs is the speed at which they can be designed and synthesized. Once the chemical structure of the RNA and the means of delivery into the body are established, synthesis of the therapy for clinical tests tends to be much faster than that of small molecule and antibody therapeutics.3 This is evidenced by the speed at which mRNA vaccines were developed during the COVID-19 pandemic.
Harnessing siRNA for rapid protection from viruses
Researchers are taking inspiration from RNA-based therapies to develop novel vaccine strategies. Dr. Shou-Wei Ding, distinguished professor of microbiology and plant pathology at University of California, Riverside, and colleagues have developed a unique live-attenuated RNA virus vaccine that induces the natural production of a large population of siRNAs.4
“Our vaccine-induced inhibition of infection mechanistically resembles RNAi therapeutics, which inhibit specific gene expression by delivering chemically synthesized siRNAs,” Ding previously told Technology Networks. “Our vaccines induce the natural production of a large population of siRNAs to target all viral RNAs for degradation. We have demonstrated full protection in mutant mouse strains without a functional adaptive immune system.”
This vaccine strategy does not require the body to have traditional immune active proteins. The researchers propose the strategy could be particularly useful in young infants and adult patients with underdeveloped or compromised adaptive immunity.
“The induction of virus-targeting siRNAs by our vaccines offers an additional layer of protection by RNAi, which induces efficient protection much quicker (2 days vs 1–4 weeks) in babies with underdeveloped immune systems or individuals with a compromised immune system,” explained Ding.
Unlike traditional vaccines that induce strain-specific protection by recognizing a few regions of a viral surface antigen, “thousands of virus-targeting siRNAs are induced by our vaccines to recognize virtually all regions of the viral RNAs, which should be able to recognize all or most strains of a virus,” said Ding.
The researchers believe there is little chance of a virus mutating to avoid this vaccination strategy, which could allow for the creation of a “one-and-done” vaccine for any number of viruses.
“It’s likely that many human viral pathogens including dengue, Zika, COVID-19 and flu, whether or not there are available approved vaccines, will be targeted for developing similar viral suppressors of RNAi-deficient, live-attenuated vaccines by researchers in academia and commercial companies.”
Delivering on the promise of RNA therapies
Despite the clear benefits of RNA-based therapies, significant obstacles continue to limit their widespread usage. Challenges include off-target effects, manufacturing at scale, immunogenicity, stability and accessibility.
“One of the critical challenges is identifying the optimal therapeutic cargo in combination with the appropriate delivery system,” Dr. Yizhou Dong, the Mount Sinai Endowed Professor in Nanomedicine at the Icahn School of Medicine at Mount Sinai told Technology Networks. “Factors such as manufacturing scalability, cost-effectiveness and regulatory approvals play a crucial role in translating these therapies from the lab to clinical practice.”
Achieving efficient and targeted RNA delivery to target organs and tissues outside the liver remains one of the most significant hurdles RNA-based medicines face. To overcome this, researchers have developed various strategies for targeted RNA delivery including using lipid nanoparticles (LNPs), virus-like particles and extracellular vesicles.5
“Delivery remains one of the most significant challenges in RNA-based therapeutics. My goal is to integrate novel chemical and engineering strategies to enhance the efficient and safe delivery of various RNA molecules. By developing innovative LNP platforms, we aim to improve tissue specificity, stability and therapeutic efficacy, ultimately expanding the potential of RNA medicines,” said Dong.
In a recent paper, Dong sought to assemble LNPs for mRNA delivery to the brain, a notoriously hard-to-target organ.6 “RNA delivery to the brain is particularly challenging due to the blood-brain barrier (BBB), which limits the passage of macromolecules,” explained Dong.
“Inspired by small molecular ligands capable of crossing the BBB, we designed and developed a novel strategy for blood–brain-barrier-crossing lipid nanoparticles (BLNPs). This technology enables the systemic delivery of a wide range of RNA molecules for diverse CNS disorders. Our approach greatly enhances delivery efficiency to the brain while maintaining biocompatibility and safety for repeated administration,” he continued.
The BLNPs developed by Dong and his team present a promising platform for delivering RNA therapies to the central nervous system. The researchers continue to work with LNPs in the hope of improving RNA delivery to other organs.
“Beyond the central nervous system (CNS), we are also constructing novel LNP formulations for targeted delivery to other organs and specific cell types to maximize therapeutic efficacy and minimize off-target effects,” Dong said.
Another promising strategy for delivering RNA-based drugs is through chemical modification. These modifications can include changes to the nucleic acid backbone, ribose ring and the nucleobase itself to optimize drug-like characteristics.7
Advances in RNA chemistry, nanocarrier systems and the advent of AI-driven drug discovery are helping RNA therapeutics reach their full potential. The question is no longer whether RNA therapies work, but how can we optimize them, so that they work better, for more patients.
“In recent years, RNA therapeutics have advanced at an unprecedented pace,” concluded Dong. “I am excited about blood–brain barrier-crossing conjugates, an innovative platform designed to enhance the delivery of biologics to the brain, paving the way for new therapeutic approaches to CNS disorders. In the near future, we anticipate critical clinical data that will guide the next generation of RNA medicines.”
1. Alhamadani F, Zhang K, Parikh R, et al. Adverse drug reactions and toxicity of the Food and Drug Administration–approved antisense oligonucleotide drugs. DMD. 2022;50(6):879-887. doi: 10.1124/dmd.121.000418
2. Zhu Y, Zhu L, Wang X, Jin H. RNA-based therapeutics: an overview and prospectus. Cell Death Dis. 2022;13(7):644. doi: 10.1038/s41419-022-05075-2
3. Kim YK. RNA therapy: rich history, various applications and unlimited future prospects. Exp Mol Med. 2022;54(4):455-465. doi: 10.1038/s12276-022-00757-5
4. Chen G, Han Q, Li WX, Hai R, Ding SW. Live-attenuated virus vaccine defective in RNAi suppression induces rapid protection in neonatal and adult mice lacking mature B and T cells. PNAS. 2024;121(17):e2321170121. doi: 10.1073/pnas.2321170121
5. Liu Y, Ou Y, Hou L. Advances in RNA-based therapeutics: Challenges and innovations in RNA delivery systems. Curr Issues Mol Biol. 2025;47(1). doi: 10.3390/cimb47010022
6. Wang C, Xue Y, Markovic T, et al. Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system. Nat Mater. 2025. doi: 10.1038/s41563-024-02114-5
7. Shi Y, Zhen X, Zhang Y, et al. Chemically modified platforms for better RNA therapeutics. Chem Rev. 2024;124(3):929-1033. doi: 10.1021/acs.chemrev.3c00611
