Exosomes – A Boon in Disguise?

The high-intensity buzz created by exosomes is by no means one that can be ignored. This widespread attention has also seeped into the specialisation of dermatology. Exosomes are being promoted for various indications such as alopecia, wound healing, hyperpigmentation, scars, and skin rejuvenation. The science behind exosomes and their mechanism of action places them as potential and promising therapeutic biopharmaceuticals. However, their present positioning in the therapeutic armamentarium of dermatologists remains gravely challenged. This viewpoint aims to make dermatologists aware of the limitations of their present placement in treatment algorithms and to disseminate accurate information about them. It does not, however, dissuade dermatologists from their use. Exosomes are extracellular nanovesicles (30–150 nm) that are diagnostic or therapeutic and are used to regenerate tissue, modulate inflammation and immunity. They are anti-apoptotic and antioxidant molecules acting by paracrine cell-to-cell communication via receptor-ligand interaction. They act on various signalling pathways intracellularly, bringing about the regulation of genes and proteins. The therapeutic benefit is due to the cargo from the parent cells, consisting of proteins, lipids, and nucleic acids, consisting of several non-coding RNAs.[1] Product-associated challenges There are presently no approved therapies using exosomes. There is no consensus on their use and dosing, or mode of administration.[2] Not all patients respond equally to the same dose, and associated epigenetic factors in a patient may play a role in the therapeutic efficacy of exosomes. Elucidation of therapeutic effects and toxicity of exosomes depends on their pharmacokinetics, about which there are no analytical standard guidelines. Elimination and accumulation profiles have not yet been elucidated despite several labelling systems due to challenges in the sensitivity and quantity capacity of exosomes.[3] The microRNA (miRNA) composition is the actual exosomal cargo that brings about biopharmaceutical action.[4] The cargo composition depends on the parent cell of origin.[5–10] Different miRNAs bring about different actions via translation of proteins or cell-to-cell communication.[11–13] The downstream effects may not always be positive. Certain miRNA signatures may be associated with disease pathobiology, and hence, not all exosomes bring about the same or positive therapeutic actions.[14] Exosomes are acellular and hence considered to be immune-privileged. However, recent studies have shown that allogenic exosomes can be immunogenic. The major histocompatibility complex (MHC) cross-dressed antigen-presenting cells, which display allogenic MHCs from exosomes on their surface, can lead to semidirect allorecognition, leading to hypersensitivity to the product.[15] Unwanted side effects and consequences due to unapproved exosome use, such as tumorigenesis, toxicity, and contamination, may also occur.[16] A serious bacterial illness in patients who received placental-derived exosome therapy in Nebraska underscores this risk. Rumors of patient deaths after exosome treatments in Japan have also created confusion regarding the safety of exosomes in the minds of the medical fraternity.[16] The magic number of exosomes that bring about a therapeutic effect is elusive and misleading. The dose escalation in billions may not always be productive, as it is known that increased numbers may implode each other, thus compromising the overall benefit. It is proposed that focus should be directed to the potency of the cargo, which will ensure inter-batch reliability and reproducibility rather than on the numbers in a product, which may include impurities in the actual numbers.[17] Another challenge is the alignment of in-vitro and in-vivo correlations.[5,8–10,18] Exosomes may not exhibit the same characteristics and hence therapeutic benefits in-vivo. Isolation challenges Exosomes are non-homogeneous, culture-sensitive products that are difficult to isolate in adequate numbers. Conventional (human and mammalian) sources and non-conventional sources from a varied group, [Table 1][4–6,8,10–12,19–21] both have their challenges. Temperature, media composition, and supplements used may all affect the final product, which poses challenges of inter-batch comparability. Exosomes isolated from the same cell type may exhibit different characteristics. The yield of production is extremely low, with less than 1 μg of exosomal protein harvested from 1 mL of culture medium.[2]Table 1: Exosome sources in developmentStorage challenges There are no fixed guidelines regarding optimal storage of exosomes. Most retain their morphological and functional characteristics at −80°C. As liquid-based exosomes are unstable, lyophilisation and cryopreservation are done to allow for longer shelf life. Both these methods lower the exosome content. Thawing may also compromise the potency of the product.[22] Regulatory challenges To date, no exosome product has been approved by the US FDA. There is no standardisation in terms of producing products with well-characterised and homogeneous exosomes; dermatologists should check for the registration of the product in ongoing and completed clinical trials and use it only for the indication approved in a clinical trial. The three major exosome databases are ExoCarta, Vesiclepedia, and EVpedia. As of 2024, only 435 studies using exosomes were registered on ClinicalTrials.gov.[23] Knowledge about the therapeutic signature and the production details of the product must be verified, making sure of the adoption of good manufacturing practices and quality control of the manufacturing facility of the product. Other concerns Gender, age, and race influence as covariates on exosome characteristics are to be researched further to predict the downstream effects and for comparison between different products in studies.[24] The recent promotion of autologous exosomes from the patient’s own blood or tissue with the use of certain devices should be met with skepticism as the isolation of exosomes is not such a simple process. Plant-derived nanovesicles are being clinically tried for dermatological indications; however, their efficacy remains a challenge. They may, however, be a safer option to eliminate oncopathogenic and immunogenic concerns. Conclusion At present, dermatologists should exercise caution and be aware of the limitations associated with the use of exosomes, especially if using products in countries lacking stringent regulatory and legislative protocols with respect to stem cells and exosome use. Good research and development by companies marketing them is essential, and the data regarding their production should be transparent and forthcoming. Engineered exosomes, no doubt, provide more precise therapeutic benefits, but large-scale production, actual purity of the product, controlled, unbiased studies, long-term risk-benefit ratio, and cost-benefit ratio are still challenges with all exosomal products. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Use of artificial intelligence (AI) Artificial Intelligence was not used in any format while preparing this manuscript.