Messenger RNA (mRNA), the short-lived molecular messenger cells use to translate DNA into protein, is now the basis of the fastest-developing therapeutic platform in medicine, starting with mRNA vaccines. Foundational work by Katalin Kariko and Drew Weissman on chemically modified nucleosides, published in Immunity in 2005, allowed synthetic mRNA to avoid triggering an immune reaction and earned them the 2023 Nobel Prize in Physiology or Medicine. That advance, together with lipid nanoparticle delivery, underpinned the Pfizer-BioNTech and Moderna COVID-19 vaccines and now supports late-stage programs against influenza, respiratory syncytial virus (RSV), and personalized cancer.
mRNA is the middleman between DNA and protein
Every cell in the body carries a full set of DNA instructions in its nucleus. When a cell needs to make a specific protein, it copies the relevant instruction into a short, disposable strand of messenger RNA and sends that copy to the cellular machinery that assembles proteins. The mRNA is read, the protein is made, and the mRNA is then broken down within hours to days. This flow, DNA to RNA to protein, is one of biology’s most fundamental rules.
An mRNA vaccine or medicine hijacks this system for a defined purpose. Instead of the body’s own instructions, it delivers a synthetic mRNA that codes for a chosen target: a viral protein, a tumor-specific mutation, a missing enzyme. The cell makes the protein briefly, the immune system sees it, and a response is trained without ever exposing the person to a live pathogen or altering their own DNA.
Two long-running problems held the field back
The idea is decades old. Two barriers kept it in the lab. First, synthetic mRNA triggered a violent inflammatory response, because the immune system is built to treat any loose RNA as a sign of viral infection. Second, mRNA falls apart quickly and cannot get through a cell membrane on its own.
Kariko and Weissman solved the first problem in the mid-2000s by swapping in modified nucleoside letters, particularly pseudouridine, which the immune system does not react to as strongly. The work spent years in obscurity before drug developers grasped its importance. The second problem was solved by lipid nanoparticles, tiny fatty bubbles that wrap the mRNA and fuse with cell membranes to deliver their contents inside.
COVID-19 proved the platform at scale
The Pfizer-BioNTech vaccine (BNT162b2) and the Moderna vaccine (mRNA-1273) were both designed within days of the SARS-CoV-2 genome being published in January 2020. Both showed roughly 95% efficacy against symptomatic COVID-19 in their pivotal randomized trials (Polack et al., NEJM 2020; Baden et al., NEJM 2021), and their safety profile has held across billions of doses. Beyond the public health outcome, the deployment proved that mRNA medicines could be designed, tested, manufactured, and distributed on a global scale in under a year, a speed no other vaccine platform has matched.
The next wave targets other infections
The COVID-19 result unlocked investment across the field. mRNA vaccines against seasonal influenza, RSV, and cytomegalovirus (CMV) are in late-stage trials. The pitch is speed: because designing a new mRNA vaccine is largely a software-and-manufacturing problem rather than a biology problem, updated versions can be produced quickly to keep pace with a mutating pathogen. That was already tested during the pandemic, when reformulated boosters against later variants moved from sequence to shipment in months.
The most striking use so far is personalized cancer vaccines
The idea of a cancer vaccine is old. What is new is the ability to make one for each individual patient. Every tumor carries a distinct set of mutations that produce abnormal proteins called neoantigens. Modern sequencing can read a patient’s tumor, pick out the neoantigens most likely to draw an immune response, and design an mRNA that codes for a bespoke selection of them, all within weeks.
The lead candidate is Moderna and Merck’s mRNA-4157, tested in adults with high-risk melanoma after tumor removal. In the phase 2b KEYNOTE-942 trial, adding the personalized vaccine to the immunotherapy drug pembrolizumab reduced the risk of recurrence or death by 44%, and the risk of distant metastasis by 65%, compared with pembrolizumab alone (Weber et al., Lancet 2024). The trial authors concluded that “adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile.” A three-year follow-up presented in 2024 showed the benefit widened over time. Phase 3 trials in melanoma and non-small cell lung cancer are underway. A separate approach from BioNTech, autogene cevumeran, has produced early signals of activity in pancreatic cancer, one of the hardest tumors to treat.
What the evidence cannot yet answer
The mRNA cancer vaccine results, though promising, come from a phase 2b trial with 157 patients and short follow-up relative to the natural history of the disease. The phase 3 trials will test whether the benefit holds in larger populations and translates into longer overall survival, not just recurrence-free survival. The manufacturing question is also unresolved: making a bespoke vaccine per patient works at trial scale, but scaling it to routine cancer care will require faster sequencing, faster synthesis, and payer models that can cover a treatment made once for one person.
References
- Kariko K, Buccini M, Ni H, et al. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity, 2005; 23: 165-175. DOI: 10.1016/j.immuni.2005.06.008
- Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. New England Journal of Medicine, 2020; 383: 2603-2615. DOI: 10.1056/NEJMoa2034577
- Baden LR, El Sahly HM, Essink B, et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. New England Journal of Medicine, 2021; 384: 403-416. DOI: 10.1056/NEJMoa2035389
- Weber JS, Carlino MS, Khattak A, et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. The Lancet, 2024; 403: 632-644. DOI: 10.1016/S0140-6736(23)02268-7
- Nobel Prize in Physiology or Medicine 2023, awarded to Katalin Kariko and Drew Weissman. Available at: nobelprize.org