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

Year: 2026

Type: review

Abstract: RNA therapeutics have emerged as a promising and effective tool to treat a wide range of genetic, metabolic, infectious, and neurodegenerative diseases by directly modulating the gene expression or directing transient protein production. Currently, more than 20 RNA-based drugs have been approved by the FDA, and due to their recent introduction into the clinical practice, long-term safety data remain limited and comparisons of adverse effects across platforms are lacking. This review focuses on the three major RNA therapeutic platforms, including antisense oligonucleotides (ASOs), small interfering RNA (siRNA) and messenger RNA (mRNA) and intends to provide a cross-platform analysis of their adverse effects. We searched studies published up to June 2026 in PubMed, Scopus, Web of Science, and Google Scholar using terms related to RNA therapeutics, individual drug names, safety and toxicity outcomes. Clinical trials, extension studies, pharmacovigilance reports, regulatory documents, and prescribing information were considered for each FDA-approved ASO, siRNA and mRNA agent. The observed safety profiles are associated with an interaction between RNA modality and additional determinants, including chemical modification, delivery system, route of administration, biodistribution, target tissue, and clinical context. Innate immune activation represents a potential shared mechanism, whereas sequence-dependent off-target effects, delivery-associated reactions, administration-related complications, and organ-specific toxicities differ in relevance and mechanism among ASO, siRNA, and mRNA therapeutics. Although most reported adverse effects are mild to moderate, important research gaps regarding long-term safety, pediatric use and rare adverse effects still exist, underscoring the need for further optimization of RNA drug design and delivery technologies, as well as continued pharmacovigilance.

Source: Frontiers in Pharmacology

DOI: 10.3389/fphar.2026.1935318