Xuling Luo,1,* Xiaoting Zhang,1,* Aibo Xu,2,3,* Yimin Yang,2,3 Wei Xu,3 Min Cai,4 Peng Xu,5 Zhen Wang,2,3 Youmin Ying,1 Kaiqiang Li2,3 

1College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, People’s Republic of China; 2Center for Laboratory Medicine, Allergy Center, Department of Transfusion Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, 310014, People’s Republic of China; 3Key Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang Province, Hangzhou, Zhejiang, 310063, People’s Republic of China; 4Hangzhou Zhongmeihuadong Pharmaceutical Co., Ltd, Hangzhou, 310011, People’s Republic of China; 5Department of Clinical laboratory, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310011, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Youmin Ying; Kaiqiang Li, Email ymying@zjut.edu.cn; likaiqiang@hmc.edu.cn

Introduction: Garcinia mangostana L. a widely used tropical fruit, has been historically valued as a medicinal plant. Modern pharmacological research has identified several compounds in its pericarp, such as alkaloids, flavonoids, and phenolic acids, which possess antioxidant and anticancer properties. Recent studies have shown that various medicinal and edible plant-derived nanovesicles (MEPNs) exhibit potent anti-tumor effects. However, the impact of Garcinia mangostana L.-derived exosome-like nanoparticles (GELNVs) in treating glioma remains insufficiently explored.
Methods: GELNVs were isolated from the rind of Garcinia mangostana L. using an environmentally sustainable method. The chemical composition of GELNVs was systematically characterized through both qualitative and quantitative analyses via UPLC-MS/MS. Network pharmacology was utilized to identify potential anti-glioma targets, with a focus on the PI3K-Akt signaling pathway. Subsequently, in vitro experiments were conducted to assess the uptake of GELNVs by glioma cells and their anti-tumor effects, including apoptosis induction, cell proliferation suppression, and effects on microglial polarization.
Results: Using a sustainable extraction method, GELNVs were successfully isolated and chemically characterized by UPLC-MS/MS. Network pharmacology and molecular docking identified key anti-glioma targets, particularly AKT1 within the PI3K-Akt signaling pathway. In vitro experiments demonstrated that GELNVs were effectively internalized by GL261 glioma and BV2 microglial cells, showing significant anti-glioma activity by inducing apoptosis and inhibiting cell proliferation. Additionally, GELNVs promoted the activation of M1-type microglia while inhibiting M2 polarization induced by IL-4 and glioma cells. This was evidenced by the upregulation of inflammatory mediators, including iNOS, TNF-α, IL-6, and IL-1β at the mRNA level.
Conclusion: Our findings demonstrate that GELNVs represent a potential therapeutic strategy for glioma by inducing apoptosis in tumor cells and inhibiting their proliferation through suppression of the PI3K-Akt signaling pathway. Furthermore, GELNVs show promise in modulating microglial polarization, further highlighting their potential as a glioma treatment.

Keywords: plant-derived exosome-like nanoparticles, glioma, microglia, Akt, network pharmacology, molecular docking