Exosomes

Exosomes are small extracellular vesicles (30-150 nm in size) that play a critical role in cellular communication by transporting proteins, lipids and nucleic acids between cells. ^[1] They are produced within multivesicular bodies and released into the extracellular space when the multivesicular body merges with the plasma membrane, and they are secreted by almost all cell types. ^[2] Their cargo includes proteins, lipids, cell surface receptors, enzymes, cytokines, transcription factors and nucleic acids such as microRNAs. ^[2] Exosomes are enriched in a group of conserved proteins, including tetraspanins (CD81, CD63, CD9), heat shock proteins (HSP70, HSP90) and biogenesis-related proteins (ALIX, TSG101). ^[3] Reported size definitions differ between reviews, with some describing exosomes as lipid bilayer vesicles 30-200 nm in diameter. ^{[4] [5]} The International Society for Extracellular Vesicles guidance (MISEV2018) recommends the generic terms small, medium and large EVs based on size or density rather than the classic term exosome. ^[5] Platelet-derived exosomes constitute a major subpopulation of circulating plasma exosomes, accounting for approximately 75% of the total exosomal content. ^[6]

Exosomes released by donor cells can subsequently modulate the function of recipient cells through the proteins, lipids and nucleic acids they carry. ^[7] The immunomodulatory effect of mesenchymal stem cells (MSCs) is primarily attributed to the paracrine pathway, and MSC-derived exosomes, as key paracrine effectors, are considered capable of reproducing MSC function as a cell-free alternative to stem cell therapy. ^{[5] [8]} In skin aging relevant to skin healthspan, in vitro and preclinical studies attribute the effects of stem cell-derived exosomes to decreased matrix metalloproteinase expression, increased collagen and elastin production and modulation of intracellular signaling. ^[7] Exosomes are also part of aging biology itself, since extracellular vesicles are among the components of the senescence-associated secretory phenotype released by senescent cells. ^[9]

Their biocompatibility, stability, low toxicity and capacity to exchange molecular cargo have made exosomes candidates for tissue engineering and regenerative medicine. ^[2] Preclinical evidence predominates: anti-inflammatory, anti-aging and wound-healing effects of MSC-derived exosomes have been shown in various in vitro and in vivo models. ^[12] Preclinical studies suggest that exosomes may support hair growth by stimulating dermal papilla cells, activating hair follicle stem cells and promoting angiogenesis, but very limited data are available on their safety and efficacy in human subjects. ^[13] A review of exosome use in human subjects included 48 studies, a substantial share of which were case reports (14) and case series (4). ^[13] One dermatology review states that clinical investigations have substantiated the regenerative efficacy of stem cell-derived exosomes in skin repair and that exosomes are being explored as biomarkers and therapeutic agents in psoriasis and vitiligo. ^[3]

There are currently no US Food and Drug Administration (FDA) approved exosome products on the market for medical indications. ^{[14] [1]} The FDA has indicated that patients in Nebraska treated with unapproved products advertised as exosome-based reported severe adverse effects, and that some clinics misled patients with claims of preventing and curing diseases. ^[15] Side effects were rare among patients treated with exosomes for hair loss, but in the broader field of dermatology at least 10 serious adverse events have been reported. ^[13] Topical exosomes applied to intact skin are generally considered safe in humans, while clinical trials are still needed to confirm long-term safety and efficacy. ^{[14] [1]} Products differ in source and isolation method, and reviews cite inconsistent isolation, purification, storage and reproducibility as unresolved challenges for clinical use. ^[1]