Orally administered royal jelly-derived extracellular vesicles exhibited liver-accumulating properties in H22 tumor-bearing mice and demonstrated moderate antitumor efficacy by modulating the immune microenvironment, gut microbiota, and PI3K/AKT signaling pathway to promote tumor cell apoptosis.
Key Findings
Results
RJEVs were successfully isolated from royal jelly and demonstrated liver-accumulating properties following oral administration in H22 tumor-bearing mice.
RJEVs were isolated and characterized as extracellular vesicles derived from royal jelly
In vivo model used H22 tumor-bearing mice
Oral administration route was used, suggesting stability through gastrointestinal passage
Liver-targeting/accumulating properties were observed, which is relevant given the hepatocellular carcinoma tumor model
Results
Orally administered RJEVs demonstrated moderate antitumor efficacy against hepatocellular carcinoma in the H22 tumor-bearing mouse model.
Antitumor effects were characterized as 'moderate' in efficacy
The H22 tumor-bearing mouse model was used as the in vivo experimental system
Effects were observed following oral administration of RJEVs
RJEVs were identified as key bioactive components contributing to the anti-HCC effects of royal jelly
Results
RJEVs enhanced both immune and antioxidant responses in H22 tumor-bearing mice.
Immune responses were enhanced following oral RJEV administration
Antioxidant responses were also improved
These effects were assessed as part of the mechanistic investigation into anti-HCC activity
Immune microenvironment remodeling was identified as a key component of the antitumor mechanism
Results
RJEVs increased the abundance of Muribaculaceae and modulated overall gut microbiota composition.
Specifically, Muribaculaceae abundance was increased following RJEV treatment
Broader gut microbiota composition was modulated
Short-chain fatty acid metabolism was also improved
Gut microbiota analysis was a specific focus of the mechanistic analyses performed in this study
Results
RJEVs promoted tumor cell apoptosis through synergistic regulation of translation-related signaling networks and the PI3K/AKT signaling pathway.
Mechanistic analysis included examination of translation-related signaling networks
The PI3K/AKT signaling pathway was specifically identified as a mediator of apoptosis
Immune microenvironment remodeling acted in concert with PI3K/AKT pathway modulation to promote tumor cell apoptosis
Conclusions
RJEVs were identified as important bioactive constituents of royal jelly that contribute to its previously reported anti-HCC effects.
This study positions RJEVs as a key active component explaining the anti-HCC properties of royal jelly
The findings provide 'novel insights into the functional role of royal jelly'
The study offers 'both theoretical and methodological advances in research on the bioactive components of bee products'
Prior to this work, the specific bioactive components of royal jelly responsible for anti-HCC activity had not been fully characterized
What This Means
This research suggests that royal jelly — a substance produced by honey bees — contains tiny nano-sized particles called extracellular vesicles (EVs) that may help fight liver cancer. When these royal jelly-derived extracellular vesicles (RJEVs) were given orally to mice with liver tumors, they traveled to and accumulated in the liver, showed a moderate ability to slow tumor growth, and triggered cancer cell death. This provides a possible explanation for why royal jelly has been previously observed to have anti-cancer properties, as RJEVs appear to be a key active ingredient responsible for these effects.
The researchers found that RJEVs work through multiple mechanisms simultaneously. They boosted the immune system's ability to fight the tumor, improved the body's antioxidant defenses, and altered the composition of gut bacteria — particularly increasing a beneficial bacterial family called Muribaculaceae — which in turn improved the production of short-chain fatty acids, molecules known to support immune and metabolic health. At the molecular level, RJEVs interfered with a specific cancer-promoting signaling pathway (PI3K/AKT) that tumors commonly use to survive, ultimately pushing cancer cells toward self-destruction (apoptosis).
This research matters because it identifies a specific component within royal jelly that may be responsible for its reported health benefits against liver cancer, offering a more precise target for future therapeutic development. The finding that these vesicles survive oral administration and naturally home to the liver makes them potentially interesting as a delivery vehicle or natural therapeutic agent. However, this work was conducted in mice, and further research would be needed to determine whether similar effects occur in humans.
Chi X, Jia L, Wang Y, Liu C, Wang S, Liu Z, et al.. (2026). Royal Jelly-Derived Extracellular Vesicles: Key Bioactive Components Mediating Anti-Hepatocellular Carcinoma Activity.. International journal of nanomedicine. https://doi.org/10.2147/IJN.S609268