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Exosomes: Highway to drug delivery in skin, reality or utopia?

Updated: Dec 28, 2023




Imagine you work in a company that provides a delivery service. Your job is to travel, contact specific customers (you must meet them face-to-face), and deliver a code to take the first step in project execution. Consider that the project starts only when the right code is delivered to the right agent. Communication must be fast, secure, and specific. In this sense, to work splendidly, you need good means of transportation, the right target, and the right code.


The human body works similarly, we are a complex machine involving cells and constant communication. Cells produce the right signals to be transported and delivered for the regulation of several cellular responses. If we think of it from a pharmaceutical point of view, the molecule in charge of triggering biological reactions would be the “code” to be delivered, and the delivery system would be the “means of transportation”. This is where biology and technology converge with design exosomes.


Exosomes are nano-extracellular vesicles (40-100 nm) containing biomolecule signals -lipids, proteins, DNAs, miRNAs, and others(1)- that are exchanged between cells and engaged in the regulation of physiological and pathological processes(2), as schematically represented below.


Schematic representation of exosome biogenesis by Yang, Gi Hoon et al.

Exosomes: possible applications, advantages, and disadvantages


Exosomes exhibit a versatile profile for therapeutic applications(3–6).

The content of these carriers depends on the parental cell type, physiological state, and cellular release site, which in turn is related to their influence on biological activity(7).


It has been demonstrated that exosomes shuttle between skin cells -Keratinocytes, fibroblasts, endothelial cells, adipocytes, and immune cells-(8). Through the mediation of cell-to-cell communication, exosomes exert influence on immune and inflammatory responses, tissue regeneration, and differential expression profile, among other regulatory mechanisms(8). For these reasons, exosomes are considered to endow therapeutical value in processes such as hair growth(9,10), pigmentation regulation(11), skin aging(8), scar removal(8), inflammatory skin diseases(8,12–14) and wound healing(4,6).


On the other hand, since exosomes are biological structures intended to transport functional molecules, it has been a topic of interest to study them as loading and subsequently as a target delivery system(15). As endogenous carriers, exosomes present desirable advantages for this role, such as:


  • Targeting capacity: Provided by bioactive membrane proteins that allow the interaction between the target and exosome(15).


  • Biocompatibility and biostability: As carriers with an endogenous origin, exosomes are endowed with non-immunogenic properties and are less likely to be phagocyted by macrophages and microglia exhibiting longer half-life compared to other synthetic nanocarriers, such as liposomes(15,16).


  • Alternative option: Potential in vivo delivery platform alternative to synthetic nanocarriers (16).


Sounds too good to be true?


Along with natural advantages, come natural limitations that must be overcome to achieve viable therapeutic applications. Exosome engineering proposes some features subjected to enhancement.


First, improvement of target capability(16), promoting the movement of exosomes to a particular tissue or cell type. Secondly, enhancing the loading of exogenous functional molecules(16), thus leading to an increase in their concentration either in the lumen or display on the surface of exosomes. Finally, the enrichment of endogenous molecules(16).


Several approaches have been studied to achieve these goals:


- Direct exosome engineering, in which exosomes are the starting material, and engineering occurs after exosome isolation(16). Loading of functional molecules is performed by mechanical and chemical methods. Such as electroporation, sonication, incubation, or bioconjugation(16).


- Parental cell-based exosome engineering uses parental cells as starting material, whereas genetic engineering occurs before the isolation of exosomes from cells(16).

i) For displaying proteins of interest (POI) on the surface of exosomes, the most common method uses an exosomal surface protein containing a signal peptide.  Once in a proper environment, the signal peptide will fuse with the protein of interest displaying it on the surface of the exosome. 
ii) For loading therapeutic molecules into the lumen of Exosomes, different methods use sorting modules for sorting molecules of interest -mostly proteins and RNAs- and conduct them to exosomes, leading to a specific loading of molecules. 

In conclusion, exosomes are a promising system with potential therapeutic value, for clinical and pharmaceutical applications. Even though there have been considerable improvements, some challenges remain unconquered. Further studies to understand exosomal potential toxicity and composition content are required(17) Purification and heterogeneity of manufactured exosomes need to be addressed(16). The development of effective technics for loading and isolation of exosomes with a cost reduction for bulk production remains a work in progress(8,16).


However, it is a matter of time until every piece comes into place to fully explode these fascinating biological materials.


References

1. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Vol. 367, Science. American Association for the Advancement of Science; 2020.

2. N V Lakshmi Kavya A, Subramanian S, Ramakrishna S. Therapeutic applications of exosomes in various diseases: A review. Materials Science and Engineering C. Elsevier Ltd; 2021.

3. Munagala R, Aqil F, Jeyabalan J, Kandimalla R, Wallen M, Tyagi N, et al. Exosome-mediated delivery of RNA and DNA for gene therapy. Cancer Lett. 2021 May 1;505:58–72.

4. Li D, Wu N. Mechanism and application of exosomes in the wound healing process in diabetes mellitus. Diabetes Res Clin Pract [Internet]. 2022 May;187:109882. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0168822722006957

5. Nasser MI, Masood M, Adlat S, Gang D, Zhu S, Li G, et al. Mesenchymal stem cell-derived exosome microRNA as therapy for cardiac ischemic injury. Vol. 143, Biomedicine and Pharmacotherapy. Elsevier Masson s.r.l.; 2021.

6. Prasai A, Jay JW, Jupiter D, Wolf SE, el Ayadi A. Role of Exosomes in Dermal Wound Healing: A Systematic Review. Journal of Investigative Dermatology. 2022 Mar 1;142(3):662-678.e8.

7. Than UTT, Leavesley DI, Parker TJ. Characteristics and roles of extracellular vesicles released by epidermal keratinocytes. Vol. 33, Journal of the European Academy of Dermatology and Venereology. Blackwell Publishing Ltd; 2019. p. 2264–72.

8. Xiong M, Zhang Q, Hu W, Zhao C, Lv W, Yi Y, et al. The novel mechanisms and applications of exosomes in dermatology and cutaneous medical aesthetics. Vol. 166, Pharmacological Research. Academic Press; 2021.

9. Semsarzadeh N, Andrasik W, Khetarpal S. Stem Cells and Exosomes in Aesthetic Medicine. Advances in Cosmetic Surgery. 2021 May;4(1):59–70.

10. Zhou L, Wang H, Jing J, Yu L, Wu X, Lu Z. Regulation of hair follicle development by exosomes derived from dermal papilla cells. Biochem Biophys Res Commun. 2018 Jun 2;500(2):325–32.

11. Liu Y, Xue L, Gao H, Chang L, Yu X, Zhu Z, et al. Exosomal miRNA derived from keratinocytes regulates pigmentation in melanocytes. J Dermatol Sci. 2019 Mar 1;93(3):159–67.

12. Cho B, Kin j, Ha D, Yi Y. Exosomes derived from mesenchymal Stem cells alleviate atopic dermatitis by suppressing inflammation and improving skin barrier function. Cytotherapy. 2019;21(5):e4.

13. Miranda M, Avila IP, Esparza J, Lowry WE. 756 Untangling G-protein-coupled receptor signaling and Creb in hair follicle homeostasis [Internet]. Available from: www.jidonline.org

14. Arzt C, Fang H, Grasmann E, Kals C, Bayer E, Auer D, et al. A CD73 ENZYME ACTIVITY ASSAY FOR STABILITY AND DOSE-FINDING OF THERAPEUTICALLY-ACTIVE EVS.

15. Fu S, Wang Y, Xia X, Zheng JC. Exosome engineering: Current progress in cargo loading and targeted delivery. Vol. 20, NanoImpact. Elsevier B.V.; 2020.

16. Jafari D, Shajari S, Jafari R, Mardi N, Gomari H, Ganji F, et al. Designer Exosomes: A New Platform for Biotechnology Therapeutics. Vol. 34, BioDrugs. Adis; 2020. p. 567–86.

17. Kimiz-Gebologlu I, Oncel SS. Exosomes: Large-scale production, isolation, drug loading efficiency, and biodistribution and uptake. Journal of Controlled Release [Internet]. 2022 Jul;347:533–43. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0168365922002905





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