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INTERNATIONAL CONGRESS OF

CancerGenetics

• The Emerging Role of Plant, Animal, and Microbial Exosomes for Targeted Cancer Drug Delivery

• SARVIN REZVANI BAFROYEH,¹ ZAHRA NOROUZIAN,² NASER FARROKHI,^3,*
  1. Shahid Beheshti University
  2. Shahid Beheshti University
  3. Shahid Beheshti University
  
  
  
• Introduction: Cancer is a leading global health issue, causing approximately 10 million deaths in 2020, with projections of 16.3 million by 2040. Traditional treatments, including chemotherapy and immunotherapy, often result in side effects due to their lack of specificity, harming healthy tissues. Consequently, there is a growing need for improved drug delivery systems. Extracellular Vesicles (EVs), particularly exosomes, present a promising alternative due to their biocompatibility and ability to transport diverse therapeutic cargo with minimal immune response. Exosomes play critical roles in cellular communication and are involved in cancer processes, serving both diagnostic and therapeutic functions. Here, we summarized the potential use of exosomes as vehicles for cancer drugs.
• Methods: Isolation: One of the crucial challenges in EV research is its isolation and the topic is under constant development. Common techniques include ultracentrifugation, density gradient centrifugation, ultrafiltration, size exclusion chromatography (SEC), immunoaffinity capture, tangential flow filtration (TFF), and polymer precipitation. Each technique has its pros and cons. More advanced methods like microfluidics, lipid nanoprobes, and thermo-acoustofluidic separation have emerged to enhance exosome isolation efficiency. Drug Loading Techniques: Exosome drug loading can be categorized into passive and active methods. Passive loading, such as co-incubation, is straightforward but often less effective. Conversely, active loading techniques—including ultrasound, electroporation, and freeze-thaw cycles disrupt the exosome membrane to facilitate drug incorporation; thus, they require careful handling to maintain integrity. Alternative methods, like saponin-assisted loading and transfection, also enhance drug uptake. Active methods typically accomplish higher drug concentrations, but maintaining exosome integrity is crucial for effective therapy. Exosome Targeting: Several strategies can enhance exosome targeting in cancer treatment, including surface modification, genetic engineering, drug loading, nanoparticle fusion, and donor cell preconditioning. In this regard, monoclonal antibodies (mAbs) are being explored to improve targeting. Moreover, folate-conjugated therapeutics that target the folate receptor are used to target many cancer cells. Engineered exosomes have been used to target both T-cell surface CD3 and the cancer-associated epidermal growth factor receptor (EGFR) demonstrating effective killing of breast cancer cells.
• Results: Plant-Based Exosomes: Plant exosomes bearing bioactive compounds with antioxidative and anti-inflammatory properties are easily produced in large quantities. They are well-tolerated in the human body, exhibiting low toxicity and minimal immunogenicity. Their stability in the gastrointestinal tract enhances efficacy for oral administration, and they can extend drug circulation time at their target sites. They also have the potential to cross the blood-brain barrier (BBB) and can be applied on the skin. However, challenges include variability in lipid composition compared to animal exosomes, limited research, and extraction difficulties. Animal-Derived Exosomes: Animal-derived exosomes present advantages for therapeutic use. They are biocompatible, have low toxicity, and can carry diverse bioactive molecules. As biomarkers for cancer diagnosis, they facilitate non-invasive liquid biopsies using proteins and microRNAs associated with cancers, such as PD-L1 and miR-15b-3p. Nevertheless, challenges exist, such as insufficient clinical-grade production, variability in composition, and low yield and purity from extraction methods. These factors, coupled with limited drug loading efficiency, potential immunogenicity, and regulatory hurdles, indicate the need for further research. Microbial Exosomes: Microbial exosomes, particularly bacterial extracellular vesicles, offer innovative approaches for cancer treatment. They can target cancer cells and are adaptable for personalized therapies. BEVs maintain stability under physiological conditions, can encapsulate various biomolecules, and be engineered for improved targeting and reduced immunogenicity. Their rapid bacterial proliferation and advanced culturing techniques enable cost-effective high-yield production. Yet, challenges such as production difficulties, immunogenicity concerns, regulatory issues, and heterogeneous properties affecting drug loading and pharmacokinetics pose obstacles. Additionally, limited knowledge of host-bacterial interactions remains.
• Conclusion: In conclusion, exosomes, particularly plant-derived exosomes, exhibit substantial promise as natural nanocarriers for cancer therapy. They effectively maintain drug potency and half-life, possess natural cell permeability, and can bypass barriers while evading lysosomal degradation. While animal and microbial exosomes have therapeutic applications, plant-derived exosomes stand out due to their natural origin and freedom from zoonotic pathogens. Emerging studies highlight their safety and effectiveness across various drug delivery routes, demonstrating abilities to enhance chemotherapy, target cancer cells, and overcome drug resistance. For instance, ginger EVs can deliver miRNAs to reduce lung inflammation, while bitter melon EVs enhance chemotherapy effectiveness for oral cancers.
• Keywords: Antioxidants, Anti-inflammation, Cancer Therapy, extra-vesicular bodies, microfluidics