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Blood exosomes-based targeted delivery of cPLA2 siRNA and metformin to modulate glioblastoma energy metabolism for tailoring personalized therapy

Zhan, Qi, Yi, Kaikai, Cui, Xiaoteng, Li, Xueping, Yang, Shixue, Wang, Qixue, Fang, Chuan, Tan, Yanli, Li, Lijie, Xu, Can, Yuan, Xubo, Kang, Chunsheng·2022·Neuro-Oncology
DOI 10.1093/neuonc/noac071
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Abstract

Background: Targeting glioblastoma (GBM) energy metabolism through multiple metabolic pathways has emerged as an effective therapeutic approach. Dual inhibition of phospholipid and mitochondrial metabolism with cytoplasmic phospholipase A2 (cPLA2) knockdown and metformin treatment could be a potential strategy. However, the strategic prerequisite is to explore a carrier capable of co-delivering the therapeutic combination to cross the blood-brain barrier (BBB) and preferentially accumulate at the GBM site. Methods: Blood exosomes (Exos) were selected as the combination delivery carriers. The cellular uptake of Exos and the therapeutic effects of the combination strategy were evaluated in primary GBM cells. In vivo GBM-targeted delivery efficiency and anti-GBM efficacy were tested in a patient-derived xenograft (PDX) model. Results: Here, we showed that the Exos-mediated cPLA2 siRNA/metformin combined strategy could regulate GBM energy metabolism for personalized treatment. Genomic analysis and experiments showed that polymerase 1 and transcript release factor (PTRF, a biomarker of GBM) positively regulated the uptake of Exos by GBM cells, confirming the feasibility of the delivery strategy. Further, Exos could co-load cPLA2 siRNA (sicPLA2) and metformin and co-deliver them across the BBB and into GBM tissue. The mitochondrial energy metabolism of GBM was impaired with this combination treatment (Exos-Met/sicPLA2). In the PDX GBM model, systemic administration of Exos-Met/sicPLA2 reduced tumor growth and prolonged survival. Conclusions: Our findings demonstrated that Exos-based combined delivery of sicPLA2 and metformin selectively targeted the GBM energy metabolism to achieve antitumor effects, showing its potential as a personalized therapy for GBM patients.

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Metadata

Authors
Zhan, Q., Yi, K., Cui, X., Li, X., Yang, S., Wang, Q., Fang, C., Tan, Y., Li, L., Xu, C., Yuan, X., & Kang, C.
Venue
Neuro-Oncology
Publisher
Oxford University Press (OUP)
Published
2022-03-21
Volume
24
Issue
11
Pages
1871-1883
ISSN
  • 1522-8517
  • 1523-5866
DOI
10.1093/neuonc/noac071
Cited by
103
References
4
Language
en
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Funders
  • National Natural Science Foundation of China (81772667, 51773151)
  • Tianjin Key R&D Program (20YFZCSY00360)
  • Tianjin Science and Technology Program (20YFZCSY00360)
  • Hebei Natural Science Foundation Precision Medicine Joint Project (H2020201206)
  • National Key Research and Development Program of China (2018YFA0209700)

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CoChat. (2026). Citation check: Blood exosomes-based targeted delivery of cPLA2 siRNA and metformin to modulate glioblastoma energy metabolism for tailoring personalized therapy. https://app.cochat.ai/papers/10.1093/neuonc/noac071
The paper
Zhan, Q., Yi, K., Cui, X., Li, X., Yang, S., Wang, Q., Fang, C., Tan, Y., Li, L., Xu, C., Yuan, X., & Kang, C. (2022). Blood exosomes-based targeted delivery of cPLA2 siRNA and metformin to modulate glioblastoma energy metabolism for tailoring personalized therapy. Neuro-Oncology. https://doi.org/10.1093/neuonc/noac071