Adverse effects of intravenous LNP-mediated mRNA therapy in clinical trials: a systematic review and meta-analysis
Wenhan Wu1,2, Ziwei Wang2
1School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, Shanghai, China.
Introduction:
Intravenous LNP-mediated mRNA therapy holds promise for treating various diseases, yet its safety, particularly regarding adverse events, remains a critical concern. This review systematically evaluates the adverse effects associated with this therapeutic approach.
Methods:
A comprehensive search of PubMed was conducted for clinical trials on intravenous LNP-mediated mRNA therapies. Data extraction focused on study design, participant demographics, and adverse events. Meta-analysis was performed to assess the incidence of treatment-emergent adverse events (TEAEs) and common manifestations. The risk of bias was assessed using the ROBINS-I tool.
Results:
A total of six phase 1/2 clinical trials on intravenous LNP-mediated mRNA therapies were included, with sample sizes ranging from 6 to 38 participants. The pooled incidence of TEAEs was 92.2% (95% CI: 77.7%-99.4%). Sensitivity analysis indicated that excluding one study with a single smaller dose reduced heterogeneity to 6.8%. The incidence of severe TEAEs was 9.2% (95% CI: 0%-38.1%) and showed substantial heterogeneity (I2 = 89.87%), which was likely influenced by factors such as higher doses, multiple administrations, and patient-specific conditions like comorbidities.
Conclusion:
While low-dose, single-dose intravenous LNP-mediated mRNA therapies generally have a manageable safety profile, higher doses or repeated administrations may increase the risk of severe adverse events.
Protocol Registration:
www.crd.york.ac.uk/prospero identifier is CRD42025643741.
Insights
Intravenous lipid nanoparticle (LNP)-mediated mRNA therapies show high rates of treatment-emergent adverse events (TEAEs), with severe events occurring in 9.2%. Lower doses appear safer, while higher or repeated doses increase risks.
Area of Science:
- Biomedical Sciences
- Pharmacology
- Gene Therapy
Background:
- Intravenous lipid nanoparticle (LNP)-mediated mRNA therapy is a promising treatment modality.
- Assessing the safety and adverse events of this therapy is crucial for clinical application.
Purpose of the Study:
- To systematically review and evaluate the adverse effects of intravenous LNP-mediated mRNA therapies.
- To determine the incidence of treatment-emergent adverse events (TEAEs) and severe TEAEs.
Main Methods:
- A systematic literature search was conducted on PubMed for relevant clinical trials.
- Data on study design, participant demographics, and adverse events were extracted.
- Meta-analysis was used to pool incidence data, and risk of bias was assessed.
Main Results:
- Six phase 1/2 trials involving 6-38 participants were analyzed.
- The pooled incidence of TEAEs was 92.2%, with severe TEAEs at 9.2%.
- Significant heterogeneity in severe TEAEs was observed, potentially due to dose, administration frequency, and patient comorbidities.
Conclusions:
- Intravenous LNP-mRNA therapies generally exhibit a manageable safety profile at low, single doses.
- Higher doses or repeated administrations are associated with an increased risk of severe adverse events.
- Further research is needed to optimize dosing and administration for improved safety.
