Royal Jelly-Derived Extracellular Vesicles: Key Bioactive Components Mediating Anti-Hepatocellular Carcinoma Activity

  • Int J Nanomedicine. 2026 Jun 3:21:609268. doi: 10.2147/IJN.S609268.
Xuepeng Chi  1  2  3 ,  Lingyu Jia  1  2  3 ,  Ying Wang  1  2  3 ,  Chao Liu  4 ,  Shuai Wang  5 ,  Zhenguo Liu  1  2  3 ,  Ge Zhang  1  2  3 ,  Baohua Xu  1  2  3
Affiliations
  • 1. Key Laboratory of Efficient Utilization of Non-Grain Feed Resources (Co-Construction by Ministry and Province), Shandong Agricultural University, Tai'an, Shandong, People's Republic of China.
  • 2. Shandong Provincial Key Laboratory of Animal Nutrition and Efficient Feeding, Shandong Agricultural University, Tai'an, Shandong, People's Republic of China.
  • 3. Department of Animal Science, Shandong Agricultural University, Tai'an, Shandong, People's Republic of China.
  • 4. Department of Minimally Invasive Oncology, Tai'an City Central Hospital, Tai'an, Shandong, People's Republic of China.
  • 5. Beekeeping Division, Shandong Provincial Animal Husbandry and Veterinary Bureau, Ji'nan, Shandong, People's Republic of China.
PMID: 42261358 DOI: 10.2147/IJN.S609268
Abstract

Purpose: To investigate the role of royal jelly derived extracellular vesicles (RJEVs) as key active components contributing to the anti-hepatocellular carcinoma (HCC) effects of royal jelly and to elucidate the underlying mechanisms.

Patients and methods: This study used H22 tumor-bearing mice as an in vivo model. RJEVs were isolated and identified and their effects were evaluated after oral administration. Analyses included the assessment of liver-targeting properties, immune and antioxidant responses, gut microbiota composition (specifically Muribaculaceae abundance), and short-chain fatty acid metabolism. This study also examined the influence of RJEVs on translation-related signaling networks and the Phosphatidylinositol 3-kinase (PI3K) / Protein Kinase B (Akt) signaling pathway to determine their role in promoting tumor cell Apoptosis.

Results: Orally administered RJEVs exhibited liver-accumulating properties in H22 tumor-bearing mice and demonstrated moderate antitumor efficacy. They enhanced immune and antioxidant responses, increased the abundance of Muribaculaceae, modulated gut microbiota composition, and improved short-chain fatty acid metabolism. Mechanistically, RJEVs synergistically regulate translation-related signaling networks and remodel the immune microenvironment, ultimately promoting tumor cell Apoptosis via the PI3K/Akt signaling pathway.

Conclusion: These findings provide novel insights into the functional role of royal jelly by identifying RJEVs as important bioactive constituents that contribute to the anti-HCC effects by modulating the immune microenvironment, gut microbiota, and PI3K/Akt signaling. This offers both theoretical and methodological advances in research on the bioactive components of bee products.

Keywords
PI3K/AKT signaling pathway; antioxidant; apoptosis; gut microbiota; immunomodulation.
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