Circular RNA Vaccine Shows Reduced Tumor Volume in Meta-analysis of Mouse Studies; Activity Also Observed in Human Immune Cells
Circular RNA vaccine examined in animal studies and human cell experiments
A circular RNA (circRNA) vaccine delivered by lipid nanoparticles (LNPs) showed reduced tumor volume and increased immune cell activity in an analysis of mouse studies. Separate experiments using human-derived cells also showed dendritic cell maturation and T-cell responses. This was not a clinical trial in patients, so the findings do not establish therapeutic efficacy or safety in people. The study was published in Scientific Reports in 2026.
circRNA is RNA whose two ends are joined to form a loop. This structure increases resistance to enzymes that degrade RNA from its ends, drawing interest in circRNA as a vaccine material for expressing antigen proteins. LNPs are carriers that deliver RNA into cells. This study evaluated the platform’s potential by combining a meta-analysis of existing animal experiments with in vitro experiments using human immune cells.
Differences between studies alongside reduced tumor volume
The researchers searched the literature from 2020 through October 2025 and analyzed mouse preclinical studies comprising 10 studies using tumor models and 11 using infectious disease models. They compared vaccine and control groups in each study; the antigens, disease models, and routes of administration varied.
In tumor models, tumor volume was lower in the vaccine groups than in the control groups. The pooled standardized mean difference (SMD) was −5.36, with a 95% confidence interval of −7.52 to −3.20. SMD is a measure used to combine studies with different measurement scales; it does not mean that tumors shrank by a specific percentage. Between-study heterogeneity was high (I²=70%). In the intramuscular injection subgroup, the difference in tumor volume did not reach statistical significance, so the findings do not show an effect across all routes of administration. Because route-specific results also compare different studies, they do not establish the superiority of any particular route.
The overall analysis found an increased proportion of activated T cells. In infectious disease models, increased serum antibody titers and reduced lung viral loads were reported. Body weight, however, did not differ significantly between vaccine and control groups. The absence of a body-weight difference alone cannot establish toxicity or long-term safety.
Immune responses also observed in human-derived cells
The researchers isolated monocytes and T cells from commercially obtained peripheral blood mononuclear cells from healthy people. They differentiated the monocytes into dendritic cells and introduced circRNA designed to express GFP and a FLAG tag. Degradation and purification steps were also performed to reduce the immune-stimulating effects of double-stranded RNA impurities generated during synthesis.
After treatment with LNP-circRNA, levels of CD80 and CD86, markers associated with dendritic cell maturation, increased. When these cells were cultured with T cells for 24 hours, IFN-γ responses were observed in CD4⁺ and CD8⁺ T cells. ELISpot testing also showed an increase in the number of cells secreting IFN-γ. These results support the possibility of immune activation in human-derived cells. However, this was a cell culture experiment using marker proteins; it did not establish selective responses to actual cancer antigens or tumor elimination in patients.
Further validation needed before clinical application
Between-study heterogeneity was high for the main results, and the animal-study risk-of-bias assessment included many items rated as high risk or unclear for randomization and blinding. The human cell experiments also cannot reproduce the complexity of the immune environment in the body. The follow-up duration and total number of animals across all included studies could not be clearly determined from the provided article text.
The researchers presented the therapeutic potential of circRNA vaccines, but these results alone cannot establish clinical efficacy for personalized cancer vaccines or superiority over existing vaccines. The study design and detailed results are available in the full Scientific Reports article.
Circle RNA (circRNA) is a closed-loop nucleic acid resistant to exonuclease degradation. Their enhanced stability and potential for efficient protein expression through circRNA modification render them promising novel therapeutic agents for cancer treatment. In this study, we systematically investigated the antitumor and anti-inflammatory activities of circRNA vaccines in mice, as well as their effects on activating antigen-specific immune responses, through a meta-analysis. Subsequently, we further validated the immune-activating effects of circRNA using monocytes and T cells isolated from human peripheral blood mononuclear cells. We found that circRNA induces the activation and maturation of dendritic cells, as well as the responses of CD4 + and CD8 + T cells. These findings demonstrate the potential of circRNA to exert significant effects in therapeutic cancer vaccines.
The practical value of this study is that it presents both a synthesis of animal research and responses in human-derived immune cells. The separate cell experiments examined the connections between circRNA-mediated protein expression, dendritic cell maturation, and T-cell responses, but did not validate treatment effects in patients. For researchers developing these vaccines, the findings provide a basis for assessing immune-cell, antibody, and viral measures alongside tumor volume. Differences by route of administration offer leads for follow-up comparative experiments, while reproducibility needs to be tested under controlled antigen and delivery conditions. Selective responses to actual disease antigens, toxicity, and response durability need further assessment before clinical applicability can be judged.