From lab to clinic: the evolving translational landscape of nucleic acid therapeutics

Introduction

The nucleic acids field is rapidly expanding owing to clinical breakthroughs in mRNA, oligonucleotides, and DNA therapeutics, alongside innovations in formulation and delivery. In 2024, the global market size of the nucleic acid therapeutics sector reached $2,540.9 million and is predicted to reach $8,688.2 million by 2034 [1]InsightAce Analytic. Nucleic Acid Therapeutics CDMO Market Size, Share & Trends Analysis Report By Technology (Column-Based Method, Microarray-Based Method), By Product, By End-User (Pharmaceutical Companies, Academic Research Institute, Diagnostic Laboratories), By Region, And By Segment Forecasts, 2025–2034. Mar 28, 2025. (accessed Aug 7, 2025)..

mRNA technology came into the spotlight during the COVID-19 pandemic, and is now being adapted for infectious disease, oncology, and protein replacement therapies. Oligonucleotides, including antisense (ASOs), small interfering RNA (siRNA), and aptamers, are maturing due to improved stability, potency, and tissue targeting. DNA-based therapeutics are also progressing toward greater safety and durability of expression.

Despite these advances, there are still hurdles that must be addressed in order for successful transition from laboratory to clinic. Preclinical and translational research is primarily focused on overcoming barriers to intracellular delivery, expanding extrahepatic targeting, and improving manufacturability.

This article highlights recent preclinical and translational advances in nucleic acid therapeutics, and efforts to address hurdles in targeted delivery, stability, and toxicity.

Oligonucleotides: clinical progress and delivery innovations

Jimmy Weterings, Vice President, Head of Oligonucleotide Therapeutics, Bonito Biosciences

“The oligonucleotide industry is as vibrant as ever. We see an increased expansion of early-stage oligonucleotide therapeutics in new tissues and indications, most particularly into CNS diseases and obesity, using a wider range of delivery vehicles. Looking forward to the day all tissues are unlocked!”

Oligonucleotide-based therapies are quickly advancing, with nearly 300 clinical trials underway across various countries [2]GlobeNewswire. Oligonucleotide Synthesis Market Research Report 2024–2035: close to 300 clinical trials (75,000+ enrolled patients) have been registered to investigate oligonucleotide based-therapeutics. Mar 18, 2025. (accessed Aug 7, 2025). . ASOs, siRNAs, and other oligonucleotide therapies are benefiting from refined chemistries and novel conjugates that enhance their potency and extrahepatic delivery.

The preclinical and translational R&D field for oligonucleotide therapies mainly focuses on overcoming delivery and stability challenges. Several candidates, such as ASOs targeting neurodegenerative diseases, are already progressing toward early-phase clinical trials [3]Harris GA, Hirschfeld LR. Antisense oligonucleotides provide optimism to the therapeutic landscape for tauopathies, Neural Regen. Res. 2024; 20, 803–804. .

For example, in July 2025, Biogen and Stoke Therapeutics presented data on zorevunersen, an investigational ASO treatment for Dravet syndrome [4]Biogen. Biogen and Stoke Therapeutics announce presentation of data from studies of zorevunersen, an investigational medicine for Dravet syndrome at the 16th European Paediatric Neurology Society Congress. Jul 10, 2025. Biogen Inc. (accessed Aug 7, 2025). . Results from Phase 1/2a and open-label extension studies showed significant and sustained reductions in major motor seizure frequency when added to standard care. The data also demonstrated improvements in cognition and behavior, supporting zorevunersen’s potential as a disease-modifying therapy for Dravet syndrome.

Similarly, Aicuris has recently presented pharmacokinetic data from the first-in-human Phase 1 trial of AIC468, an ASO targeting the BK virus. The trial involving healthy volunteers showed AIC468 was well tolerated with favorable absorption and distribution [5]Aicuris. Aicuris presents pharmacokinetic data from the first in human clinical trial of AIC468, a novel antisense oligonucleotide targeting BK virus, at World Transplant Congress. Aug 5, 2025. (accessed Aug 7, 2025)..

With nearly 2,170 therapies in development, the oligonucleotide therapeutics field is rapidly expanding, but challenges such as tissue-specific delivery, off-target effects, and high manufacturing costs must be addressed to further advance the space [6]Beacon Intelligence. Disease Trends in the Oligonucleotide Space. Apr 2025. (accessed Aug 7, 2025)..

mRNA therapeutics: advancing beyond vaccines

Piotr Kowalski, Senior Lecturer in Advanced Therapies, University College Cork

“Despite recent challenges in advancing prophylactic mRNA vaccines, therapeutic applications of mRNA continue to demonstrate strong progress, particularly in gene editing and cancer therapeutics. Novel modalities, including circular and self-amplifying mRNAs, are broadening the scope of mRNA technology and opening new therapeutic avenues.”

Beyond vaccines for infectious diseases, mRNA platforms are advancing in oncology, rare diseases, central nervous system disorders, and other indications [7]Parhiz H, Atochina-Vasserman EN, Weissman D. mRNA-based therapeutics: looking beyond COVID-19 vaccines. Lancet 2024; 404, 1192–1204. Parhiz H, Atochina-Vasserman EN, Weissman D. mRNA-based therapeutics: looking beyond COVID-19 vaccines. Lancet 2024; 404, 1192–1204. . Major advances in computational design, novel RNA scaffolds, targeted delivery, and safety profiling are driving progress toward broader clinical impact in 2025 and beyond [7]Parhiz H, Atochina-Vasserman EN, Weissman D. mRNA-based therapeutics: looking beyond COVID-19 vaccines. Lancet 2024; 404, 1192–1204. Parhiz H, Atochina-Vasserman EN, Weissman D. mRNA-based therapeutics: looking beyond COVID-19 vaccines. Lancet 2024; 404, 1192–1204. .

For instance, a study published in 2025 identified phosphoserine aminotransferase 1 (PSAT1) as a key factor in cardiac repair following myocardial infarction (MI) [8]Magadum, A., Mallaredy, Roy R, et al. Phosphoserine aminotransferase 1 promotes serine synthesis pathway and cardiac repair after myocardial infarction, Theranostics 2025; 15, 7219–7241. (accessed Aug 7, 2025). . Researchers administered synthetic PSAT1-modified mRNA to mice post-MI, resulting in significant cardiomyocyte proliferation, reduced scar formation, and improved cardiac function. These findings suggest that PSAT1 could be a promising target for mRNA-based therapies in ischemic heart diseases.

Additionally, in 2025, mRNA-based therapies continued to advance through the clinical pipeline, with several candidates entering mid-stage trials. For instance, Ethris has recently started a Phase 2a clinical trial for ETH47, an mRNA-based antiviral therapy aimed at preventing asthma exacerbations caused by respiratory viruses [9]Ethris. Ethris doses first patient in Phase 2a clinical trial of lead mRNA candidate ETH47 for asthma. Aug 5, 2025. (accessed Aug 7, 2025). . The study will enrol 50 adult asthma patients who will receive ETH47 or a placebo following a controlled rhinovirus challenge.

However, despite the clinical progress, there are still challenges in the mRNA therapeutics field that must be addressed, such as improving delivery efficiency and stability, and managing the potential immunogenicity of mRNA to avoid adverse immune reactions [7]Parhiz H, Atochina-Vasserman EN, Weissman D. mRNA-based therapeutics: looking beyond COVID-19 vaccines. Lancet 2024; 404, 1192–1204. . Advances in lipid nanoparticle (LNP) technology and chemical modifications are helping to overcome these barriers.

Exploring DNA vaccine pipelines

Christian Ottensmeier, Professor of Immuno-oncology, University of Liverpool

“DNA-based immunotherapeutics / DNA vaccines are beginning to deliver real clinical impact in numerous pre-malignant and malignant disease settings. In HPV-driven respiratory papillomatosis, the DNA vaccine developed by Inovio has just been granted accelerated approval by the US FDA. Additionally, a DNA-based personalised cancer vaccine has delivered meaningful clinical benefit in patients with hepatocellular carcinoma in a trial reported by Geneos; in this setting, immunotherapy had, by and large, failed to impact outcome to date prior to this trial. It is clear, therefore, that DNA as a platform for the delivery of antigens to improve immunotherapy is taking its place in the rapidly changing field of cancer immunotherapy.”

Beyond oligonucleotide and mRNA-based therapeutics, DNA vaccine pipelines are also expanding and diversifying, with improved vector engineering, synthetic DNA designs, and safer integration strategies driving broader clinical translation.

In April 2025, NHS England announced that it is fast-tracking advanced melanoma patients for the iSCIB1+ cancer vaccine trial, part of the Cancer Vaccine Launch Pad (CVLP) program [10]NHS England. Skin cancer patients given fast-tracked access to ‘revolutionary’ cancer vaccine trial on NHS. Apr 14, 2025. (accessed Aug 7, 2025). . The needle-free DNA vaccine aims to enhance the immune system’s ability to better target melanoma cells and improve immunotherapy outcomes. Patient referrals have started in May 2025, and the SCOPE Phase II trial will expand across multiple NHS sites this year. The CVLP aims to offer personalized cancer vaccines to 10,000 patients by 2030.

Therapeutic DNA vaccines are also gaining traction in indications beyond oncology, reflecting broader clinical potential. For example, PharmaJet and Immuno Cure have recently partnered to advance ICVAX, an HIV-1 therapeutic DNA vaccine, utilizing PharmaJet’s Tropis^® needle-free intradermal delivery system [11]11.PharmaJet. PharmaJet^® and Immuno Cure Sign Agreement for Clinical Development of a Needle-free HIV Therapeutic DNA Vaccine. Jun 19, 2025. (accessed Aug 7, 2025). . Following a successful Phase 1 trial demonstrating excellent safety and promising immune responses, this collaboration aims to improve vaccine efficacy by targeting immune cells in the skin.

In summary, DNA vaccines have become a key strategy for preventing and treating contemporary biomedical diseases, yet, similarly to oligonucleotides and mRNA, developing an effective delivery system continues to be the primary challenge in this field [12]Lu B, Lim JM, Yu B, et al. The next-generation DNA vaccine platforms and delivery systems: advances, challenges and prospects. Front. Immunol. 2024; 15,1332939. .

Advances in formulation and delivery

John Lewis, Chief Executive Officer, Entos Pharmaceuticals

“Genetic medicine is approaching a pivotal inflection point. While recent advances in molecular biology have enabled us to target the root cause of disease with unprecedented control and accuracy, a critical bottleneck remains: the safe, efficient, and tissue-specific delivery of nucleic acid-based therapeutics. Current clinically approved delivery platforms present inherent limitations, including immunogenicity, toxicity, limited tissue tropism, and challenges with redosing. To fully harness the therapeutic potential of genetic medicines, the field must advance next-generation delivery systems that are non-immunogenic, redosable, and capable of precise biodistribution across diverse cell types and tissues.”

LNPs, polymeric carriers, and ligand-conjugated systems are evolving to overcome nucleic acid delivery bottlenecks, achieve tissue-specific targeting, and enable repeat dosing with reduced immunogenicity. Many companies are exploring different lipid chemistries and novel technologies such as artificial intelligence (AI) to design delivery systems that target extrahepatic tissues.

In July 2025, Etherna introduced a novel bio-reducible LNP platform designed to efficiently deliver mRNA to bone marrow stem cells and T cells. This delivery system aims to address existing bottlenecks in targeting extra-hepatic tissues, enhancing the potential of mRNA therapeutics for hematological diseases. The platform offers improved delivery efficiency with reduced toxicity. Etherna plans to further develop and apply this technology in clinical programs targeting blood and immune disorders.

Furthermore, METiS Technologies recently unveiled its AiLNP platform, an AI-driven system designed to optimize LNP formulations for nucleic acid delivery [13]FirstWord Pharma. METiS Technologies showcases AI-powered nanodelivery platform at the 2025 Controlled Release Society Annual Meeting. Jul 22, 2025. (accessed Aug 7, 2025). . The platform utilizes a de novo lipid generation approach, enabling the development of LNPs with improved delivery efficiency and reduced toxicity profiles. AiLNP aims to advance the design of LNPs for mRNA and gene therapies, addressing challenges in targeting extra-hepatic tissues and enhancing therapeutic outcomes. METiS plans to integrate AiLNP into its development pipeline to accelerate the creation of next-generation LNP formulations.

Summary

The nucleic acid therapeutics field is advancing rapidly, driven by breakthroughs in molecular design, targeted delivery, and growing clinical momentum across diverse disease areas. Oligonucleotides and mRNA therapies are expanding into new indications with improved chemistries and delivery systems, while DNA vaccines are gaining traction in oncology. Despite all this progress, challenges such as achieving consistent extrahepatic delivery, minimizing immune responses, and scaling up manufacturing without compromising stability still exist. However, ongoing innovation in lipid chemistry, formulation strategies, and data-driven design continues to push the field forward, bringing nucleic acid therapeutics closer to broader clinical impact

References

1. InsightAce Analytic. Nucleic Acid Therapeutics CDMO Market Size, Share & Trends Analysis Report By Technology (Column-Based Method, Microarray-Based Method), By Product, By End-User (Pharmaceutical Companies, Academic Research Institute, Diagnostic Laboratories), By Region, And By Segment Forecasts, 2025–2034. Mar 28, 2025. (accessed Aug 7, 2025).

2. GlobeNewswire. Oligonucleotide Synthesis Market Research Report 2024–2035: close to 300 clinical trials (75,000+ enrolled patients) have been registered to investigate oligonucleotide based-therapeutics. Mar 18, 2025. (accessed Aug 7, 2025).

3. Harris GA, Hirschfeld LR. Antisense oligonucleotides provide optimism to the therapeutic landscape for tauopathies, Neural Regen. Res. 2024; 20, 803–804. 

4. Biogen. Biogen and Stoke Therapeutics announce presentation of data from studies of zorevunersen, an investigational medicine for Dravet syndrome at the 16th European Paediatric Neurology Society Congress. Jul 10, 2025. Biogen Inc. (accessed Aug 7, 2025). 

5. Aicuris. Aicuris presents pharmacokinetic data from the first in human clinical trial of AIC468, a novel antisense oligonucleotide targeting BK virus, at World Transplant Congress. Aug 5, 2025. (accessed Aug 7, 2025).

6. Beacon Intelligence. Disease Trends in the Oligonucleotide Space. Apr 2025. (accessed Aug 7, 2025).

7. Parhiz H, Atochina-Vasserman EN, Weissman D. mRNA-based therapeutics: looking beyond COVID-19 vaccines. Lancet 2024; 404, 1192–1204.

8. Magadum, A., Mallaredy, Roy R, et al. Phosphoserine aminotransferase 1 promotes serine synthesis pathway and cardiac repair after myocardial infarction, Theranostics 2025; 15, 7219–7241. (accessed Aug 7, 2025).

9. Ethris. Ethris doses first patient in Phase 2a clinical trial of lead mRNA candidate ETH47 for asthma. Aug 5, 2025. (accessed Aug 7, 2025).

10. NHS England. Skin cancer patients given fast-tracked access to ‘revolutionary’ cancer vaccine trial on NHS. Apr 14, 2025. (accessed Aug 7, 2025).

11. 11.PharmaJet. PharmaJet^® and Immuno Cure Sign Agreement for Clinical Development of a Needle-free HIV Therapeutic DNA Vaccine. Jun 19, 2025. (accessed Aug 7, 2025). 

12. Lu B, Lim JM, Yu B, et al. The next-generation DNA vaccine platforms and delivery systems: advances, challenges and prospects. Front. Immunol. 2024; 15,1332939.

13. FirstWord Pharma. METiS Technologies showcases AI-powered nanodelivery platform at the 2025 Controlled Release Society Annual Meeting. Jul 22, 2025. (accessed Aug 7, 2025).