Prodrug suicide gene therapy for cancer targeted intracellular by mesenchymal stem cell exosomes

Area of Science:

• Oncology
• Cell Biology
• Biotechnology

Background:

• Mesenchymal stem cells (MSCs) exhibit natural tumor-targeting properties.
• Exosomes, secreted vesicles from MSCs, are being explored for therapeutic delivery.
• Engineering MSCs with suicide genes offers a potential strategy for targeted cancer therapy.

Purpose of the Study:

• To investigate the therapeutic potential of exosomes derived from engineered human tumor-tropic MSCs expressing a suicide gene (yCD::UPRT-MSCs).
• To determine if these engineered exosomes can induce tumor cell death in the presence of a prodrug.
• To explore the mechanism of action and therapeutic efficacy of MSC-derived exosomes carrying a suicide gene.

Main Methods:

• Isolation of human tumor-tropic MSCs from various tissues.
• Engineering MSCs to express the yeast cytosine deaminase::uracil phosphoribosyl transferase (yCD::UPRT) suicide gene.
• Collection of exosomes from conditioned medium of engineered MSCs.
• Treatment of tumor cells with exosomes and the prodrug 5-fluorocytosine (5-FC).
• Analysis of exosome cargo (mRNA, microRNAs) and assessment of tumor cell viability.

Main Results:

• Exosomes derived from yCD::UPRT-MSCs contained mRNA of the suicide gene.
• Internalization of these exosomes by tumor cells led to dose-dependent cell death.
• The prodrug 5-FC was intracellularly converted to 5-fluorouracil, mediating tumor cell death.
• Exosomes were identified as the primary mediators of tumor inhibitory activity.
• MicroRNA content did not significantly differ between naive and engineered MSC exosomes and was not associated with the therapeutic effect.

Conclusions:

• MSC-derived exosomes engineered with a suicide gene represent a novel class of intracellularly acting drugs for cancer therapy.
• This approach demonstrates curative potential by enabling targeted delivery of a therapeutic payload to tumor cells.
• The exosome-mediated suicide gene therapy offers a promising strategy for enhanced tumor targeting and treatment efficacy.