Extracellular vesicle-mediated suicide mRNA/protein delivery inhibits glioblastoma tumor growth in vivo

Abstract

Extracellular vesicles (EVs) are considered as important mediators of intercellular communication, which carry a diverse repertoire of genetic information between cells. This feature of EVs can be used and improved to advance their therapeutic potential. We have previously shown that genetically engineered EVs carrying the suicide gene mRNA and protein-cytosine deaminase (CD) fused to uracil phosphoribosyltransferase (UPRT)-inhibited schwannoma tumor growth in vivo. To further examine whether this approach can be applied to other cancer types, we established a subcutaneous xenograft glioblastoma tumor model in mice, as glioblastoma represents the most common primary brain tumor, which is highly aggressive compared with the original schwannoma tumor model. U87-MG glioblastoma cells were implanted into the flanks of nude SCID mice, and the animals were intratumorally injected with the EVs isolated from the cells expressing EGFP or CD-UPRT. After the intraperitoneal administration of the prodrug 5-fluorocytosine, the tumor growth was assessed by regular caliper measurements. Our data revealed that the treatment with the CD-UPRT-enriched EVs significantly reduced the tumor growth in mice. Taken together, our findings suggest that EVs uploaded with therapeutic CD-UPRT mRNA/protein may be a useful tool for glioblastoma treatment.

Exosomes for mRNA delivery: a novel biotherapeutic strategy with hurdles and hope

“…Following in vivo administration, Exo-Ts exhibit significant inhibition of tumor cell proliferation without any direct impact on other tissues and prolongation of animal survival [61]. This study displayed that the treatment with the CD-UPRT-enriched exosomes and the intraperitoneal administration of the prodrug 5-FC significantly reduced the tumor proliferation [109].…”

Through Scalp and Skull NIR‐II Photothermal Therapy of Deep Orthotopic Brain Tumors with Precise Photoacoustic Imaging Guidance

“…To construct efficient brain tumor treatment paradigms, so far, most efforts have been devoted to developing advanced therapeutic systems such as chemo and gene therapy . These methods strongly rely on sophisticated design of drug delivery systems (DDS) to transport drug/gene into tumors and realize release in a controlled manner.…”

“…These methods strongly rely on sophisticated design of drug delivery systems (DDS) to transport drug/gene into tumors and realize release in a controlled manner. However, the DDS accumulation in normal tissues often leads to unwanted side‐effects . In addition, GBM cells can rapidly develop drug resistance, which causes limitations of the available therapeutics .…”

The versatile roles and clinical implications of exosomal mRNAs and microRNAs in cancer

“…148 In addition, genetically engineered exosomes enriched with therapeutic cytosine deaminase-uracil phosphoribosyltransferase (CD-UPRT) mRNA, which is a type of suicide gene mRNA, were shown to significantly decrease tumor growth in a subcutaneous xenograft glioblastoma tumor model after intratumoral injection. 149 Although exosome-based delivery systems have bright prospects for cancer therapy, there are still challenges in this field: (a) how to improve loading efficiency; (b) how to enhance delivery efficacy and targeted uptake by recipient cells; (c) how to reduce off-target effects; and (d) how to evaluate the appropriate dose and ensure quality control. To overcome these challenges, various engineering strategies have been applied for both presecretion cells and postpurification of exosomes.…”