FDA-Approved RNA Drugs Show Mostly Mild Side Effects, But Long-Term Safety Data Remain Thin

More than twenty RNA-based medicines have now won approval from the U.S. Food and Drug Administration, transforming the treatment of genetic diseases, metabolic disorders, infections, and neurodegenerative conditions. Yet a sweeping new review of the safety records of these drugs finds that while most side effects are mild to moderate, the field still lacks the long-term safety data needed to fully characterize rare adverse events. The analysis, published in Frontiers in Pharmacology, offers the first systematic cross-platform comparison of the three dominant RNA therapeutic modalities: antisense oligonucleotides (ASOs), small interfering RNA (siRNA), and messenger RNA (mRNA).

The review, led by researchers at the University of Patras in Greece, examined eighteen FDA-approved RNA therapeutics across the three platforms. The team searched PubMed, Scopus, Web of Science, and Google Scholar for studies published through June 2026, drawing on clinical trials, extension studies, pharmacovigilance reports, regulatory documents, and prescribing information. Their central conclusion is that safety profiles cannot be explained by the RNA modality alone. Instead, adverse events emerge from an interplay between the RNA molecule’s chemistry, its delivery system, the route of administration, how the drug distributes through the body, the target tissue, and the clinical context of the patient.

Among siRNA therapeutics, which silence genes through the cellular RNA interference machinery, the dominant pattern is remarkably consistent. GalNAc-conjugated drugs such as inclisiran, lumasiran, nedosiran, and vutrisiran are delivered directly to hepatocytes and are administered subcutaneously. Their most common adverse effects are injection-site reactions, which occur in roughly five to eight percent of patients receiving inclisiran and up to thirty to forty percent of those on lumasiran. These reactions are generally mild, transient, and self-limiting. Notably, inclisiran has not been associated with the significant hepatotoxicity, renal toxicity, or muscle-related adverse effects seen with other lipid-lowering therapies such as statins.

The picture changes when siRNAs rely on lipid nanoparticles rather than GalNAc conjugation. Patisiran, the first FDA-approved siRNA, uses an LNP delivery system and is given intravenously. Approximately nineteen percent of treated patients experience infusion-related reactions despite premedication, presenting as flushing, nausea, abdominal pain, headache, and transient blood pressure changes. Because patisiran and vutrisiran both suppress the same target, transthyretin mRNA, the contrast between them is instructive: vutrisiran, delivered subcutaneously via GalNAc without an LNP carrier, avoids the infusion-related pattern entirely. The reviewers caution, however, that this should not be read as evidence that GalNAc conjugation is intrinsically safer across all RNA drugs, since product-specific chemistry, exposure, dosing, and clinical context also differ.

One pharmacodynamic consequence shared by TTR-targeting agents deserves attention. Transthyretin serves as a carrier protein for retinol-binding protein, so prolonged suppression of TTR lowers serum vitamin A levels. Both patisiran and vutrisiran require vitamin A supplementation during treatment, and eplontersen, a GalNAc-conjugated ASO against the same target, produces the same expected reduction. Givosiran, another GalNAc siRNA approved for acute hepatic porphyria, has additionally been linked to laboratory abnormalities including elevated liver enzymes, renal function changes, and hyperhomocysteinemia, findings that must be weighed against the drug’s intended hepatic action and the underlying disease.

The mRNA platform, represented by four approved vaccines, presents a distinct safety architecture. Comirnaty, Spikevax, mNEXSPIKE, and mRESVIA all use LNP delivery and intramuscular administration. The most common reactions are local and systemic responses consistent with immune activation: injection-site pain, fatigue, headache, myalgia, chills, and fever, typically resolving within a day or two. Rare but clinically significant events include myocarditis and pericarditis, occurring predominantly in adolescent and young adult males within the first week after a second dose, at an estimated rate of approximately 12.6 cases per million second doses for Comirnaty. Anaphylaxis has also been reported, with hypersensitivity to PEG-containing lipid components investigated as a potential mechanism.

Comparisons between the two original COVID-19 mRNA vaccines reveal subtle differences. Spikevax shows a lower rate of anaphylaxis, roughly 3.42 per million doses compared with 9.31 for Comirnaty, but a higher rate of non-anaphylactic hypersensitivity and cutaneous reactions, including delayed large local reactions. Some observational studies have suggested higher myocarditis rates after mRNA-1273 than after BNT162b2, but the reviewers stress that such comparisons must account for differences in age distribution, dose, dosing interval, and surveillance methods, and should not be interpreted as demonstrating an intrinsic platform-level difference. Other rare events, including Bell’s palsy, immune thrombocytopenia, transverse myelitis, and Guillain-Barré syndrome, have appeared in pharmacovigilance reports, though reporting after vaccination does not by itself establish causality.

ASO therapeutics display the most heterogeneous safety landscape of the three platforms, reflecting their varied chemistries, targets, and routes of administration. Nusinersen and tofersen are delivered intrathecally into the cerebrospinal fluid, and their most common adverse effects, lower back pain and headache, are largely attributable to the lumbar puncture procedure itself. Tofersen has been associated with serious neurological events including myelitis, radiculitis, aseptic meningitis, and papilledema, though the reviewers note that repeated lumbar puncture, local CNS exposure, inflammatory responses, and progression of the underlying SOD1-ALS may all contribute. The four phosphorodiamidate morpholino oligomers approved for Duchenne muscular dystrophy share an intravenous route, and procedural pain, catheter-site reactions, and musculoskeletal symptoms must be disentangled from the disease itself.

Two ASOs stand out for their more serious toxicity profiles. Inotersen, approved in 2018 for hereditary transthyretin amyloidosis, has been linked to severe thrombocytopenia and glomerulonephritis, complications requiring dedicated laboratory monitoring and thought to involve immune-mediated mechanisms. Eteplirsen, golodirsen, viltolarsen, and casimersen have shown rare nephrotoxicity signals, and renal surveillance remains relevant for the PMO class given preclinical renal findings and the renal handling of oligonucleotides, even though clinically significant kidney injury has not been consistently demonstrated in treated patients.

The review’s overarching message is that no RNA platform can be labeled intrinsically safer or more toxic than another. Innate immune activation represents a potential shared biological mechanism across all three classes, since exogenous RNA structures can engage pattern-recognition pathways and delivery components such as PEG can independently trigger inflammatory or hypersensitivity responses. But sequence-dependent off-target effects, delivery-associated reactions, and organ-specific toxicities differ in relevance and mechanism among ASOs, siRNAs, and mRNAs. The authors emphasize that safety assessment must be product-specific, accounting for the entire therapeutic architecture from sequence and chemical modification through delivery, administration, tissue exposure, and clinical application. They also flag persistent gaps: long-term safety data remain limited for recently approved products, evidence in pediatric and other underrepresented populations is incomplete, and pharmacovigilance data are susceptible to under-reporting and confounding. As clinical exposure grows, continued pharmacovigilance, long-term extension studies, and individualized risk-benefit evaluation will be essential to the responsible use of the next generation of RNA medicines.

Subject of Research: Cross-platform analysis of adverse effects of FDA-approved ASO, siRNA, and mRNA therapeutics

Article Title: Adverse effects of FDA-approved RNA therapeutics: a cross-platform analysis of RNA design, delivery systems, and safety profiles

Article References: Stamatopoulou, V., Kouvela, A., Ahtypi, K., Douka, E., Kominatou, C., Meimaroglou, A., Spyropoulou, K., Taxari, S., Theodoridou, S., & Plotas, P. (2026). Adverse effects of FDA-approved RNA therapeutics: a cross-platform analysis of RNA design, delivery systems, and safety profiles. Frontiers in Pharmacology, 17, Article 1935318. https://doi.org/10.3389/fphar.2026.1935318

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1935318

Keywords: RNA therapeutics, antisense oligonucleotides, siRNA, mRNA vaccines, adverse effects, FDA approval, drug safety, lipid nanoparticles, GalNAc conjugation, pharmacovigilance, toxicity, drug delivery