Understanding Mechanisms of Polygonatum Sibiricum-Derived Exosome-Like Nanoparticles against Breast Cancer through An Integrated Metabolomics and Network Pharmacology analysis

Tingwen Ming¹Yang Yang²Bing Shang³Zhihao Li¹Fangling Ren¹Lun Wu¹Shuya Zhang²Jun Zhu¹Qinhua Chen²Jingjian Liu^1*

• ¹Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan, China
• ²Shenzhen Baoan Authentic TCM Therapy Hospital, Shenzhen, China
• ³Institute of Medical Information, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing Municipality, China

Background: Research has found that plant-derived exosome-like nanoparticles (PELNs) have enormous potential in the field of biomedicine, such as serving as natural nanomedicines to treat diseases or as carriers for drug delivery. However, there are no studies on PSELNs against cancer.Methods: This work used ultracentrifugation to extract the PSELNs and characterized them using TEM, NTA, and DLS. Proteomics and metabolomics were used to analyze the components of the PSELNs. Network pharmacology was used to analyze the possible mechanisms of the PSELNs against BC, mainly including PPI network analysis for potential targets, GO for analyzing biological processes, and KEGG for analyzing related signaling pathways. After that, the related data of BC was retrieved from the GEO database, and the clinical expression and survival prognosis of the key genes screened by network pharmacology were analyzed by bioinformatics. Molecular docking and MD simulation were used to verify the binding of active metabolites in the PSELNs with their targets. Finally, the CCK-8 method was used to validate the inhibitory effect of the PSELNs on BC.Results: Firstly, TEM, NTA, and DLS confirmed that the PSELNs were successfully isolated. Then, Proteomics identified 18 protein components from the PSELNs. Metabolomics identified 357 metabolic components from the PSELNs and further screened 23 active metabolites by OB, it was speculated that the PSELNs may have pharmacological activity against BC. After that, network pharmacology was used to screen 23 key targets of the PSELNs against BC. These 4 targets were validated by molecular docking and MD simulation with active metabolites in the PSELNs, and it was found that the binding of sedanolide and ESR1, Baicalein and PPARG, and 6-Gingerol and ESR1 can remain stable. Finally, The inhibitory effect of the PSELNs on BC cells (MDA-MB-231) was validated by the CCK-8 method.This was the first time that the PSELNs have been studied against cancer. It was verified that they have anti-BC activity, and the mechanism may be related to targets such as ESR1 and PPARG, regulated by active metabolites in the PSELNs.