Current landscape of clinical trials for mRNA-based therapeutics

ABSTRACT

Beyond coronavirus disease 2019 (COVID-19) vaccines, messenger RNA (mRNA)-based therapeutics have increasingly demonstrated potential across other treatment areas. To summarize the clinical research landscape for such products and provide valuable references for researchers working in related fields, mRNA clinical trials registered on ClinicalTrials.gov (CTg) and the Chinese Clinical Trial Registry (ChiCTR) up to June 7, 2025, were analyzed. Twelve key items, including registration number, study title, target disease, interventions, blinding, sponsor, phases, enrollment, funder type, study type and start date, and locations, were analyzed to describe trial characteristics. A total of 557 clinical trials of mRNA-based therapeutics were identified. Most of these studies were conducted in phases 0–3 (n = 412, 73.97%), primarily focusing on infectious diseases (n = 410, 73.61%), and predominantly open-label designs (n = 338, 60.68%). Interventional studies accounted for 85.82% (n = 478) of all registered trials. Industry sponsors were the primary source of funding (n = 299, 53.68%). Approximately 45.06% of the projects (n = 251) aimed to enroll 0–100 participants. Most of the studies involved mRNA vaccines (n = 507, 91.02%). Further, 22 trials investigated mRNA-based therapeutics for rare diseases. Among the newly registered projects in 2024 and 2025, the proportion of phase 0–1 trials significantly increased, accounting for 61.67% and 78.13%, respectively. The top three regions that conducted mRNA clinical studies were North America (n = 186; primarily the United States [n = 178]), Asia (n = 184; China [n = 72]), and Europe (n = 90), based on studies registered in both CTg and ChiCTR. Most mRNA products remain in preapproval clinical trials. Further phase 3 clinical evidence will be essential to support its broader application.

Introduction

Messenger RNA (mRNA) is a single-stranded ribonucleic acid that carries genetic information and directs protein synthesis. It serves as a template for protein production on the ribosome, identifying the amino acid sequence of the peptide chain, and is characterized by transient expression. The development of mRNA biotechnology has been a lengthy process, involving contributions from several scientists. In the 1950’s and 1960’s, a series of experiments identified the associations among DNA, RNA, and proteins.¹ In a landmark study in 1987, Malone et al. revealed that mRNA molecules mixed with lipid droplets could enter cells and express target proteins. This marked the beginning of mRNA-based drug research.²

Compared with other pharmacological modalities, including small molecules, proteins, and DNA, mRNA-based therapeutics provide distinct advantages. First, mRNA molecules are rapidly designed using bioinformatic tools and synthesized through chemical processes, thereby enabling fast, cost-effective, and scalable production.³ Second, the mechanism of mRNA is straightforward, presenting lower development risks and significantly shortening the research and development (R&D) timeline.^4,5 However, challenges remain, particularly in delivery and molecular instability. Efficient delivery of mRNA to target cells introduces a major challenge due to its large molecular size and negative charge, which hinder its passage across the cell membrane. Moreover, mRNA is highly susceptible to degradation with ribonucleases in vivo, especially in the bloodstream, where it demonstrates a short half-life. This instability complicates the sustained pharmacological activity of injected mRNA.^6–8

To address these limitations, several strategies have been developed, including lipid nanoparticles (LNPs), polymeric nanocarriers,⁹ electroporation,¹⁰ and charge-altering releasable transporters.⁷ Since 2020, the successful global deployment of LNP-formulated mRNA coronavirus disease 2019 (COVID-19) vaccines has demonstrated the substantial potential of this technology. To date, over 10 billion doses of mRNA vaccines from Moderna and Pfizer-BioNTech have been administered globally. This achievement validates the safety and efficacy of mRNA-based interventions and paves the way for the application of LNP-mRNA platforms as a versatile macromolecular delivery system in various disease treatments. This article summarizes the clinical trials for mRNA-based products registered on the ClinicalTrials.gov (CTg) and Chinese Clinical Trial Registry (ChiCTR) databases.

Methods

The current landscape of mRNA-based clinical trials was investigated through the advanced retrieval functions of the CTg and ChiCTR databases, with “mRNA” as the key search term and a data cutoff date of June 7, 2025. The analysis included only clinical trials that investigated mRNA vaccines or mRNA-based therapeutic drugs, while excluding mechanistic studies, including those using mRNA as a biomarker. The CTg database was searched using the study title registered in ChiCTR to identify duplicate registrations and consolidate them into single entries. Twelve key items, including registration number, study title, target disease, interventions, blinding, sponsor, phases, enrollment, funder type, study type, start date, and locations, were analyzed to describe trial characteristics. Therapeutic categories were categorized based on disease system and anatomical site. Registration entries that were listed as “NK,” left blank, or contained other nonspecific terms in Chinese were consolidated into a single “NK” category.

Results

This analysis included 557 clinical trials. Among these, 498 trials (89.41%) were registered on CTg, whereas 59 trials (10.59%) were sourced from the ChiCTR database. Table 1 presents the distribution of therapeutic areas targeted by mRNA-based products in the included studies. Further, Table 2 shows the analyzed distribution of therapeutic areas in newly registered clinical trials from 2020 to 2025.

Table 1.

Therapeutic area of mRNA product.

Therapeutic area	Number of trials	Percentage(%)
Infectious disease	410	73.61
Oncology	109	19.57
Rare disease	22	3.95
Autoimmune disorder	5	0.90
Other disease	11	1.97
Total	557	100.00

Table 2.

Therapeutic areas of mRNA product from 2020 to 2025.

Year	Infectious disease, n (%)	Oncology, n (%)	Rare disease, n(%)	Autoimmune disorder, n (%)	Other diseases,a n (%)	Total, n
2020	19 (90.48)	0 (0.00)	2 (9.52)	0 (0.00)	0 (0.00)	21
2021	140 (93.33)	5 (3.33)	4 (2.67)	1 (0.67)	0 (0.67)	150
2022	110 (90.16)	9 (7.37)	3 (2.46)	0 (0.00)	0 (0.00)	122
2023	89 (62.24)	49 (34.27)	5 (3.50)	0 (0.00)	0 (0.00)	143
2024	35 (58.33)	14 (23.33)	6 (10.00)	2 (3.33)	3 (5.00)	60
2025	13 (40.63)	13 (40.63)	2 (6.25)	1 (3.13)	3 (9.38)	32

^aOther diseases included: Acne (n = 1), Heart failure (n = 2), Myasthenia Gravis (n = 2), Skin Aging (n = 1).

Regarding trial phases, 250 studies (44.88%) were categorized as phase 0–1, 241 studies (43.27%) were in phase 2–3, and 29 studies (5.21%) were phase 4 trials. The phase information was unavailable for the remaining studies. Further, the number of newly registered clinical trial projects for mRNA products during the peak R&D period from 2020 to 2025 was analyzed. The results reveal that among the newly registered projects in 2024 and 2025, the proportion of phase 0–1 trials significantly increased, accounting for 61.67% and 78.13% of the total newly registered projects, respectively. Table 3 presents detailed data.

Table 3.

Phase distribution of trials from 2020 to 2025.

Year	Phase 0–1, n (%)	Phase 2–3, n (%)	Phase 4, n (%)	NK,a n (%)	Total,b n
2020	10 (47.62)	10 (47.62)	0 (0.00)	2 (9.52)	21
2021	36 (24.00)	55 (36.67)	15 (10.00)	57 (38.00)	150
2022	44 (36.07)	53 (43.44)	5 (4.10)	30 (24.59)	122
2023	70 (48.95)	69 (48.25)	5 (3.50)	23 (16.08)	143
2024	37 (61.67)	23 (38.33)	4 (6.67)	7 (11.67)	60
2025	25 (78.13)	14 (43.75)	0 (0.00)	3 (9.38)	32

^aNK refer to no data available.

^bIf labeled as PHASE1/PHASE2, the trial is counted under both the “phase 0–1” and the “phase 2–3” categories.

Most of the included studies were open-label (n = 338, 60.68%), and interventional trials accounted for 85.82% (n = 478) of the total. Funding was primarily provided by industry sources (n = 299, 53.68%), with additional contributions from universities, hospitals, research centers, the National Institutes of Health (NIH), and other governmental agencies. Regarding the sponsors, industry sponsorship represents the largest share, accounting for about half of all projects (n = 284, 50.99%). This is followed by hospitals (n = 115, 20.65%), universities (n = 80, 14.36%), research centers (n = 38, 6.82%), and other entities, which include governmental agencies, individual researchers, and similar bodies. Approximately 45.06% of the projects (n = 251) aimed to enroll 0–100 participants. Table 4 provides a detailed breakdown.

Table 4.

Distribution of sample sizes in mRNA-based clinical trials.

Sample size (participants (n))	Number of mRNA drug trials	Percentage (%)
0–100	251	45.06
101–200	76	13.64
201–300	47	8.44
301–400	29	5.21
401–500	22	3.95
501–1000	60	10.77
>1000	79	14.18
NKa	1	0.18
Total	557

^aNK refer to no data available.

Among the included mRNA-based studies, the vast majority focused on mRNA vaccines (n = 507, 91.02%). The rare disease classification provided by the Orphanet database indicated that 22 trials investigated mRNA products that target rare diseases. Table 5 summarizes the primary rare diseases involved in these studies.

Table 5.

mRNA-based clinical trials for rare disease therapeutics.

Disease name	Number of trials
Ornithine Transcarbamylase Deficiency	5
Propionic Acidemia	2
Methylmalonic acidemia	2
Familial Hypercholesterolemia	1
Glycogen Storage Disease	2
Cystic Fibrosis	4
Glycogen Storage Disease Type III (GSD III)	1
Lyme Disease	1
Primary Ciliary Dyskinesia	2
Phenylketonuria	1
Huntington Disease	1
Total	22

Based on the geographical location of the primary research centers for clinical trials registered in both CTg and ChiCTR, the top three regions that conducted mRNA clinical studies were North America (n = 186, primarily the United States [n = 178]), Asia (n = 184, China [n = 72]), and Europe (n = 90) (Table 6).

Table 6.

Number of mRNA clinical trials by region.

Rgeion	Number of mRNA clinical trials
North America	186
Asia	184
Europe	90
Oceania	27
South America	16
Africa	8
NKa	46
Total	557

^aNK refer to no data available.

We analyzed the disease distribution in mRNA clinical studies registered during the postpandemic period (2024–2025). Clinical trials led primarily by China (n = 36) were predominantly focused on oncology (n = 25, 69.44%), with the remainder including COVID-19 (n = 2, 5.56%), other infectious diseases (n = 7, 19.44%), autoimmune diseases (n = 1, 2.78%), and myasthenia gravis (n = 1, 2.78%). Conversely, studies led primarily by the United States (n = 32) covered a broader spectrum of rare diseases, including COVID-19 (n = 8, 25.00%), other infectious diseases (n = 15, 46.88%), rare diseases (n = 5, 15.63%), oncology (n = 2, 6.25%), acne (n = 1, 3.13%), and myasthenia gravis (n = 1, 3.13%) (Table 7).

Table 7.

Number of trials in United States and China during 2024–2025.

Therapeutic area	The United States, n (%)	China, n (%)
Infectious disease	23 (71.88)	9 (25.00)
-COVID-19	8 (25.00)	2 (5.56)
-Other infectious disease	15 (46.88)	7 (19.44)
Oncology	2 (6.25)	25 (69.44)
Rare disease	5 (15.63)	0 (0.00)
Autoimmune disease	0 (0.00)	1 (2.78)
Other disease	2 (6.25)	1 (2.78)

Discussion

Currently, approximately 20 major public platforms globally, including the International Clinical Trials Registry Platform, CTg, the EU Clinical Trials Register, as well as national platforms, such as ChiCTR and the Japan Registry of Clinical Trials, accept registrations and comply with international standards. CTg is an official government database maintained by the United States NIH and is the largest and most authoritative trial registry globally. Although managed by the United States, researchers and sponsors worldwide voluntarily register their trials. Registration is mandatory for United States – based clinical trials. The registration interface is primarily in English. ChiCTR is a non‑profit institution managed and maintained by the West China Hospital of Sichuan University/Chinese Evidence-Based Medicine Center. It serves as a primary registry in the World Health Organization International Clinical Trials Registry Platform and is characterized by its academic and international nature. Its main data scope covers clinical trials conducted in China, comprising regulatory-related and investigator-initiated trials. Registration is voluntary, not mandatory, for researchers. The registration interface and most trial information are in Chinese. In this study, only research projects registered in CTg and ChiCTR were retrieved. Data on trials conducted in Europe and other countries are not fully captured. Therefore, the regional comparative analysis only compared mRNA clinical trials conducted predominantly in the United States and China.

A theoretical possibility of duplicate registration of the same trial in both databases was considered when retrieving mRNA clinical trials from CTg and ChiCTR for analysis. We searched CTg using the English study titles recorded in the ChiCTR interface and identified no duplicates. However, the possibility that researchers may have registered the same trial under inconsistent English names across the two databases – a scenario we cannot identify – cannot be ruled out.

mRNA research activities are shaped by national policies worldwide. For instance, in China, both national and local authorities have systematically positioned mRNA therapy as a cutting-edge track in biomedicine in recent years, encouraging researchers to pursue RNA drug development and providing financial support.^11,12 In December 2025, the European Commission published the proposed Biotech Act, which, for the first time, introduces a 12-month Supplementary Protection Certificate extension incentive for advanced medicines such as mRNA therapies, along with accelerated approval procedures, while shortening the review timeline for multinational clinical trials from 106 d to 75 d.¹³ The UK government has entered into a ten-year strategic partnership with Moderna, which has committed to investing over £1 billion to establish an innovation technology center in the UK; it has also partnered with BioNTech to ensure that, by 2030, 10,000 National Health Service patients will be provided with personalized mRNA-based cancer immunotherapies.¹⁴ As for the United States, according to an industry survey published in May 2025, 48% of surveyed mRNA organizations have already been affected by NIH funding cuts and anti-mRNA policies, with 20% of companies relocating projects or departments to Europe and Asia. This indirectly confirms the existence of a policy-driven “siphon effect” in other regions.¹⁵ Therefore, while the exploration of mRNA technology will persist, its geographical distribution may shift significantly. Who will lead the next wave of technological innovation remains an open question.

This study analyzed the annual number of mRNA clinical trials (Figure 1). There was a significant increase in newly registered mRNA projects in 2021. However, the number dropped to 122 in 2022, then rose to 143 in 2023. These changes likely represent typical fluctuations during a peak period of research activity. Further, a notable decrease in the number of newly registered clinical trials for mRNA products was observed in 2024 and early 2025. COVID-19 vaccine studies accounted for 68.38% (n = 266) among the trials registered between 2020 and 2023. In contrast, from 2024 to early June 2025, the proportion of COVID-19 vaccine trials decreased significantly to 18.75% (n = 15). The analysis of research sponsors shows that clinical research projects sponsored by enterprises accounted for the highest proportion, reflecting the important role they play in the development of mRNA products. Concurrently, the distribution of therapeutic areas for mRNA products from 2020 to 2025 demonstrates that the proportion of studies that were focused on infectious diseases decreased from a peak of 93.33% to 40.63%, whereas the proportion of oncology-related studies increased. This is primarily because COVID-19 vaccine research, categorized under infectious diseases, is no longer global focal point in mRNA product development. However, the foundational work on COVID-19 vaccines has broadened the therapeutic scope of mRNA technology, thereby redirecting significant efforts toward the development of preventive or therapeutic products for other indications.

Figure 1.

The number of registered mRNA-based clinical trials form 2002 to 2025.

Analysis of the changes in trial phases from 2020 to 2025 reveals a significant increase in the proportion of newly registered phase 0–1 clinical trials in 2024 and 2025. This may well reflect a global reallocation of pharmaceutical research resources, including shifts in R&D pipelines and the pursuit of emerging technologies. As we know, after the COVID-19 pandemic, pharmaceutical companies, like BioNTech and Moderna, have shifted their focus away from the active development of mRNA COVID-19 vaccines and directed more resources toward early-phase clinical trials for new mRNA products that target other indications. In its 2024 annual report, BioNTech outlined its mRNA product R&D pipeline, which includes melanoma, HPV16+ head and neck cancer, lung cancer, colorectal cancer, and other solid tumors.¹⁶ Meanwhile, in its business and pipeline update at the 44th Annual J.P. Morgan Healthcare Conference, Moderna reported that it will enter 2026 with a focus on growing sales, launching new infectious disease products, and delivering pivotal readouts across oncology, rare disease, and infectious disease portfolios.¹⁷ Concurrently, mRNA therapeutic technology is undergoing continuous innovation, particularly in chemical modification and advanced delivery systems, thereby enabling its potential application across expanding disease areas.¹⁸

Oncology represents another major disease area in mRNA-based product development. Based on distinct mechanisms of action, mRNA-based therapeutics enable diverse approaches for cancer treatment, which are categorized as antitumor mRNA vaccines and drugs. Antitumor mRNA vaccines are designed to activate the patient’s immune system, enabling the recognition and elimination of tumor cells.^19–24 Antitumor mRNA drugs include immunostimulatory cytokines,^25,26 tumor-suppressor or cytotoxic proteins,^27,28 and therapeutic antibodies.²⁹ Currently, antitumor mRNA vaccines represent a major research focus due to their potential for precise tumor targeting. However, until the present, no mRNA-based antitumor vaccines or drugs have received marketing authorization.

Moreover, the target indications for mRNA product development include rare diseases, comprising over 7,000 distinct disorders that affect a significant portion of the population. Currently, most rare diseases lack targeted therapeutic options.³⁰ Dwight Koeberl et al.³¹ conducted the first-in-human trial of an mRNA-based therapy that targets propionic acidemia. Preliminary results from 12 patients indicated the safety and potential clinical benefits of the treatment. These findings support mRNA as a highly promising platform for treating rare diseases. In this study, 22 clinical trials targeting 11 distinct rare diseases were identified. However, until the present, no mRNA drug for rare diseases has yet received marketing approval. Nevertheless, based on the mechanism of action of mRNA technology, mRNA-based therapy provides a potential approach to compensate for deficient protein production caused by genetic defects, thereby bringing new hope to patients.

The groundbreaking therapeutic potential of mRNA technology is extensively celebrated; however, it is imperative to seriously consider its associated toxicity risks. Currently, mRNA-based drugs and vaccines are commonly delivered using LNPs. LNP components, including buffer agents and small-molecule lipids, may contribute to toxicity.³² In contrast to single-dose vaccines, mRNA therapeutics frequently require repeated administration, which introduces additional toxicological concerns. The cellular tropism and tissue distribution of LNP-mRNA formulations could lead to organ-specific toxicity, and their reactogenicity remains a significant issue. Ionizable and PEGylated lipids play crucial roles in LNP-mRNA delivery but are also associated with potential toxic effects, including immune activation and the phenomenon of accelerated blood clearance. These adverse reactions originate from formulation components, manufacturing processes, and dosing regimens. Furthermore, other safety concerns may originate from clinical applications due to off-target effects or impacts on various tissues and organs. The clinical trials registered in these two databases are predominantly characterized by small-sample, open-label exploratory designs, likely reflecting the aforementioned limitations of mRNA products.

The successful application of mRNA technology in COVID-19 vaccines has attracted widespread attention, leading to the continuous emergence of mRNA-based clinical trials. Further, mRNA vaccines and drugs have demonstrated remarkable efficacy in preventing COVID-19 and mitigating severe symptoms, and their applications have expanded to various disease treatments, including respiratory conditions, rare diseases, and cancers.³² The current analysis revealed that most mRNA products are still in preapproval (phase 0–3) clinical trials. In addition to limited number of approved mRNA products globally, this indicates a highly competitive landscape in the commercialization pathway for mRNA-based pharmaceuticals.

The race for commercialization speed is, in essence, a high-pressure, multidimensional contest of technology, resources, and strategic positioning. The rapid success of COVID-19 vaccines possessed certain unique characteristics, including a well‑defined viral target and clear correlates of immune protection. However, in more complex fields – including cancer immunotherapy, genetic diseases, and autoimmune disorders – scientific uncertainty is much higher, thereby placing greater demands on the targeting ability of delivery systems and the control of immunogenicity.^4,33

Furthermore, this is not merely a competition between products but a contest of platform technologies, production efficiency, and iterative capabilities – encompassing the entire technological chain from sequence design and delivery systems to scaled-up manufacturing.² The intense competition in this field is compelling the industry to shift from a speculative mind-set focused on chasing hotspots toward a deeper cultivation model grounded in solid science, long-term planning, and differentiated innovation.

Currently, commercially available mRNA-based therapeutics primarily comprise COVID-19 vaccines, along with Moderna’s MRESVIA,³⁴ a respiratory syncytial virus vaccine, which recently received regulatory approval. Most mRNA product candidates remain in preclinical development or clinical trials.

Conclusion

In recent years, mRNA technology has achieved groundbreaking advances in the fields of vaccination and therapeutics. The success of mRNA vaccines demonstrated their potential for rapid development, high immunogenicity, and favorable safety profiles, particularly during the COVID-19 pandemic. Furthermore, mRNA differs fundamentally from traditional chemical drugs and biologics due to its unique mechanism, which enables in vivo cells to directly produce antigens, functional proteins, or repair factors. Currently, the clinical application of mRNA-based interventions has expanded beyond infectious disease prevention to encompass areas, including cancer immunotherapy, rare disease treatment, and autoimmune disorders, accompanied by a substantial increase in the number of clinical trials. Looking forward, advances in sequence design, delivery technologies, and combination therapies will help establish mRNA as a transformative platform across multiple disease domains. Further phase 3 clinical evidence will be essential to support its broader application.

Biography

Saiwei Wu obtained his M.M. from Zhejiang University in 2010. He is a Deputy Chief Pharmacist and Clinical Pharmacist at the Fourth Affiliated Hospital of Zhejiang University School of Medicine. He serves as the Assistant to the Director of the Pharmacy Department and holds several key academic and professional roles. These include being a committee member of the Clinical Pharmacy Professional Committee of the China Medical Education Association, a youth member of the Clinical Pharmacy Branch of the Zhejiang Medical Association, and a member of the Perioperative Pharmacy Committee of the Zhejiang Pharmaceutical Association. He also contributes as Vice Chairman of the Yiwu Clinical Pharmacy Committee and Deputy Director of the Yiwu Hospital Pharmacy Quality Control Center. His research primarily focuses on pharmaceutical administration, drug analysis, and the material basis of traditional Chinese medicine. His work reflects a strong commitment to advancing clinical pharmacy and pharmaceutical care.

Funding Statement

This work was financially supported by the Zhejiang Yangtze River Delta Health Research Fund Project [Grant no. 2023CSJ-2-A005].

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

Ethics statement

As the data were obtained from public databases, ethical approval is not applicable to this research.