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

Abstract

Background Targeting 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 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 patient-derived xenograft 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.

Emerging extracellular vesicle-based carriers for glioblastoma diagnosis and therapy

“…To solve these problems, Zhan et al used biological system-derived exosomes (Exos) to load sicPLA2 and metformin, yielding Exo-Met/sicPLA2 for GBM therapy. 155 A typical "saucer-like" nanomorphology was found for both the empty Exos and Exo-Met/sicPLA2, with diameters of 116.5 ± 3.2 nm and 128.1 ± 7.7 nm, respectively. It was found that PTRF expression was significantly increased in the GBMs.…”

Exosomal cargos-mediated metabolic reprogramming in tumor microenvironment

“…Although there are currently no engineered exosomes to directly target various metabolic pathways in the TME, exosomes can be combined with classical drugs or modalities as an adjuvant therapy to improve the efficacy of anti-tumor therapy. It has been shown that combination of exosome-mediated cPLA2 siRNA and metformin reduces the growth of glioblastoma xenografts by impairing the energy metabolism of mitochondria [295]. Photodynamic therapy (PDT) is a novel method of treating tumors with photosensitizing drugs and laser activation [300].…”

The Role of Long Noncoding Ribonucleic Acids in Glioblastoma: What the Neurosurgeon Should Know

“…Understanding of the impact of ribonucleic acids in both normal and disease states is continuing to rapidly expand. While understanding of microRNA 1a,2a and short-interfering RNAs 3a,4a continues to emerge, lncRNA molecules are an exciting new focus for cancer researchers, including those who study GBM. The translation of lncRNA biological knowledge into putative therapeutics has not yet been realized because of the novelty of understanding and because of the diverse roles they play in GBM tumorigenesis.…”