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INTERNATIONAL CONGRESS OF

CancerGenetics

• Engineered exosomes in cancer gene therapy

• Sara Azimi,¹ Samaneh Sharif,^2,*
  1. Department of Medical Laboratory Sciences, Faculty of Paramedical and Rehabilitation Sciences, Mashhad University of Medical Sciences
  2. Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences
  
  
  
• Introduction: Cancer is one of the most prevalent and lethal diseases globally. Currently used methods for its therapy have not fully succeeded in terms of curative outcomes and minimization of adverse effects. As a result, novel gene therapy approaches have been developed, using microRNAs, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated nuclease protein 9 (Cas9)-based technology, and immune checkpoint inhibitors, all of which depend on an effective delivery system, facilitating both cell penetration and gene expression. Exosomes have been suggested as gene delivery vectors due to their intrinsic biocompatibility, low clearance rate, and remarkable structural stability. Several studies have focused on engineering exosomes either by directly modifying them or by regulating the cellular response of donor cells to enhance their therapeutic effects. Engineering methods are generally divided into four categories: biological, immunological, physical, and chemical; each having its own advantages and disadvantages.
• Methods: Several databases, including Google Scholar, PubMed, Science Direct, Web of Science, Scopus, etc., were searched using the terms "engineered exosomes" and “cancer gene therapy”; relevant articles published since 2020 were selected and reviewed.
• Results: Engineered exosomes have been reported to deliver therapeutic payloads to cancer sites and release bioactive therapeutic molecules via targets on the surface. For example, exosome-based drug delivery can prevent the P-glycoprotein drug efflux system, which can reduce drug resistance in cancer cells. The miR-HER2 (human epidermal growth factor receptor 2)-loaded exosomes coated with ligands trigger stronger tumoricidal effects than exosomes without a targeted peptide. In a study, it was demonstrated that MSC-derived exosomes carrying miR-124 in vivo resulted in prolonged survival of mice with glioma. Anti-CD3 and anti-EGFR (epidermal growth factor receptor) antibody-engineered exosomes could promote the binding of T cells to cancer cells for precise therapy. Similarly, exosomes displaying both anti-human CD3 and anti-human HER2 antibodies can simultaneously target T-cell CD3 and breast cancer-associated HER2 receptors in breast cancer. CD63 and CD9 marker proteins expressed on the surface of exosomes are often chosen as the target proteins for exosome engineering, by which Ye et al. produced engineered exosomes that could efficiently load CRISPR-Cas9 components. Bellavia et al. genetically fused interleukin-3 (IL-3) to the N-terminal of LAMP-2B to improve the targeting ability of exosomes in chronic myeloid leukemia (CML). An in vitro experiment demonstrated that exosomes with tLyp-1-siRNAs have high delivery efficacy into both lung cancer and cancer stem cells. Chen et al. presented two types of antibodies (CD3 UCHT1 and scFv fragments of EGFR cetuximab) on the surface of exosomes, which resulted in effective antitumor immunity. In a study, the application of exosomes linked to the glioma-targeting RGE peptide (RGERPPR) resulted in the accumulation of exosomes in tumor regions, inducing a potent antitumor effect in a mouse cancer model. In breast cancer, PTX-loaded exosomes not only inhibit tumor growth but also prevent recurrence and metastasis in breast cancer-bearing mice. AntimiRNA-21 and antimiRNA-10b were loaded into polymeric nanocarriers (PNCs), and these PNCs were subsequently coated with uPA-engineered exosomes (uPA-eEVs) to enhance the tumor-targeting affinities and tumor regression, providing evidence for the combinational antitumor effects of ncRNAs and engineered exosomes. Engineered exosomes, serving as a next-generation drug delivery platform, are expected to push the frontiers in drug delivery. However, the inadequacy of mass production and purification processes has kept exosomes from entering the market.
• Conclusion: Although cancer is a well-known deadly disease, current treatments are not only ineffective but also cause side effects. On the other hand, exosomes play an undeniable role in the development of treatments, as has been demonstrated in various in vitro and in vivo studies. By modifying naturally isolated exosomes, the most suitable nanocarriers can be prepared for the purpose of treatment and delivery of the desired therapeutic agents. Surface modification alleviates reaching the recipient cells and facilitates uptake into the cells. Although several procedures are used to obtain large quantities of exosomes, there is no standard for this purpose. Thus, exosome isolation and characterization require technological progress to achieve effective and pure exosomes. Most post-loading methods and genetic modifications could harm the stability and integrity of exosomes. Therefore, for clinical application, a gold standard and universal exosome engineering method remains a challenge.
• Keywords: Engineered exosomes, cancer, gene therapy