Safety profile of small interfering RNA therapeutics: a systematic review and meta-analysis of randomized controlled trials

Objectives Small interfering RNAs (siRNAs) represent a promising therapeutic platform addressing unmet clinical needs. Recent advances have improved siRNA design, stability, specificity, and delivery; however, translating preclinical findings into clinical practice remains challenging due to the lack of standardized safety evaluation frameworks. This study conducted a systematic review and meta-analysis of placebo-controlled randomized clinical trials (RCTs) to quantitatively assess the safety of siRNA therapeutics and evaluate the adequacy of current preclinical safety assessments. Methods PubMed, Embase, and Cochrane databases were searched from inception to July 2025. Two reviewers independently performed study selection and data extraction according to predefined criteria. Safety outcomes included death, serious adverse events (SAEs), severe adverse events, and adverse events (AEs) leading to treatment discontinuation. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using R packages meta and metafor . Methodological quality for AE assessment was evaluated using the McHarm scale. The protocol was registered with PROSPERO (CRD420251120555). Results Of 5,527 records screened, 57 studies (53 reports) evaluating 28 siRNA agents were included. Compared with controls, siRNA treatment did not increase the risk of death (RR 0.77, 95% CI 0.62–0.95) and severe AEs (RR 0.85, 95% CI 0.76–0.95), with no statistical heterogeneity (I 2 = 0%). Risks of SAEs (RR 0.94, 95% CI 0.88–1.00) and treatment discontinuation (RR 0.86, 95% CI 0.66–1.13) were not increased. Conclusion Chemical and delivery advancements have effectively enhanced siRNA safety. Nevertheless, ongoing vigilance and comprehensive safety monitoring during early clinical phases remain essential to identify unforeseen toxicities. Systematic Review Registration Identifier CRD420251120555.