Introduction

In the realm of cell communication, exosomes are tiny but mighty. First identified in the 1980s as secreted vesicles from reticulocytes, these extracellular vesicles have since been recognized for their pivotal role in intercellular communication. Ranging in size from 30 to 150 nanometers, exosomes are spherical structures encapsulated in a lipid bilayer. Inside, they harbor a diverse array of biological molecules, including proteins, lipids, DNA, messenger RNA (mRNA), and microRNA (miRNA). Their stability in biological fluids makes them particularly intriguing for researchers, as they can transport vital information between cells and influence various physiological and pathological processes.

Fig. 1 Exosomes (Solomon M. C., et al. 2023).

How Exosomes Are Formed

Exosomes originate from the endosomal pathway. They form as intraluminal vesicles within the endosome, a cellular compartment involved in transporting molecules. As early endosomes mature into late endosomes (also known as multivesicular bodies), they undergo a series of transformations, eventually fusing with the plasma membrane to release their exosomal contents into the extracellular space. This process can occur via two main pathways: one that relies on the endosomal sorting complex required for transport (ESCRT) and another that does not. Factors like oxidative stress and hypoxia can influence exosome release, while certain drugs can also stimulate their production.

Exosomes as Communication Tools

Exosomes serve as unique messengers, facilitating the transfer of bioactive molecules to recipient cells. When exosomes fuse with target cell membranes, they can alter the recipient's biology by delivering proteins, signaling molecules, mRNA, and miRNA. This molecular cargo can modify cellular functions, making exosomes crucial players in various biological processes.

In the context of oral health, exosomes are abundant in saliva and other bodily fluids, representing a promising avenue for research into oral diseases and conditions. Their role in mediating communication between cells opens doors for understanding the molecular underpinnings of potentially malignant oral disorders and head and neck cancers.  

Exosomes in Oral Potentially Malignant Disorders

Recent studies have explored the role of exosomes in various oral disorders. For instance, researchers have isolated exosomes from mesenchymal stem cells derived from normal oral mucosa, dysplastic lesions, and cancerous tissues. Analysis revealed specific miRNAs, such as miR-8485, that were differentially expressed across these groups. When introduced to dysplastic cell lines, this miRNA promoted rapid growth and enhanced cellular migration and invasion-hallmarks of malignancy.

Another study showed that exosomal miR-185 could significantly reduce inflammation and dysplastic changes in a model of oral potentially malignant disorders. By targeting specific signaling pathways, this miRNA proved effective in mitigating the severity of lesions.

Exosomes in Oral Submucous Fibrosis

Oral submucous fibrosis, a precancerous condition often linked to areca nut chewing, has also been associated with exosomal activity. Researchers isolated exosomes from adipose-derived mesenchymal stem cells and found that these exosomes could downregulate collagen expression in fibroblasts, suggesting a potential therapeutic role. Notably, they inhibited the p38 MAPK signaling pathway, a crucial pathway in fibrosis, indicating their promise as a treatment option.

In a different study, long non-coding RNA (lncRNA) isolated from exosomes was shown to regulate metabolic and cancer pathways, highlighting the importance of exosomal cargo in the progression of oral submucous fibrosis.

Exosomes in Oral Lichen Planus

Oral lichen planus, a chronic inflammatory condition, has been linked to dysregulated immune responses. Exosomal analysis revealed a specific set of miRNAs that were upregulated in patients compared to healthy controls. These miRNAs can target multiple genes, potentially altering cellular behavior and contributing to the disease's pathology.

Exosomes in Oral Cancer

Exosomes from oral cancer patients have distinct characteristics. They can be larger than typical exosomes, with diameters reaching up to 400 nm. Proteomic analyses have identified a variety of proteins within these exosomes, including markers associated with cancer progression and metastasis.

Exosomes play a multifaceted role in oral cancers, facilitating tumor growth, invasion, and metastasis. They can transfer oncogenic miRNAs to non-cancerous cells, effectively transforming them into cells with malignant potential. For instance, hypoxic conditions in tumors can enhance the delivery of specific miRNAs that promote metastatic behavior in cancer cells.

Notably, exosomal contents can also mediate chemoresistance, complicating treatment options. Exosomes released by resistant cancer cells can carry miRNAs that inhibit the efficacy of chemotherapy drugs, creating challenges for successful treatment strategies.

Exosomes in Treatment Strategies

One of the most exciting applications of exosomes lies in their potential for drug delivery. Due to their natural ability to encapsulate therapeutic molecules, exosomes can serve as vehicles for targeted delivery, significantly minimizing the side effects commonly associated with traditional therapies. Their biocompatibility and stability in circulation make them ideal candidates for transporting drugs directly to tumor sites.

Exosomes can be engineered to carry a wide variety of therapeutic agents, including small molecules, proteins, and nucleic acids. Techniques for loading drugs into exosomes encompass both passive and active methods. Passive methods, such as transfection, involve introducing drugs into donor cells that subsequently package them into exosomes. Active methods, like electroporation, create temporary pores in the exosomal membrane, allowing therapeutic molecules to enter.

By utilizing exosomes as drug carriers, researchers aim to enhance the effectiveness of treatments for oral cancers while reducing toxicity to healthy tissues. The prospect of using exosomes as natural drug delivery systems is particularly promising, as their lipid bilayer membrane protects their contents from degradation and destruction, ensuring that therapeutic agents reach their intended targets.

Challenges in Exosome Research

Despite their enormous potential, several challenges impede the clinical use of exosomes. One major obstacle is the isolation process. Obtaining high-purity exosomes can be time-consuming and costly, and ensuring their quality remains a significant concern. Additionally, maintaining the stability of exosomes, especially in saliva, presents another challenge.

To ensure effective therapeutic use, it is crucial to determine the optimal dosing, delivery routes, and treatment frequency for exosome-based therapies. Extensive clinical research is necessary to confirm that these therapies are both safe and effective in real-world applications.

Conclusion

Exosomes are emerging as critical players in the understanding of oral health and cancer biology. Their unique capabilities as vehicles for molecular communication and drug delivery offer exciting possibilities for both diagnostics and therapeutics. As research continues to unravel their complexities, exosomes may one day play a pivotal role in the prevention, diagnosis, and treatment of oral diseases, offering hope for more effective and personalized healthcare solutions.