Dear editor, Radiation-induced skin injury (RSI) refers to inflammatory damage to the mucous and skin membranes caused by exposure to different types of ionizing radiation1-4. Up to 95% of people receiving radiation therapy have this serious side effect. In the days to months following radiation therapy, this collateral damage first manifests as acute radiation dermatitis, which is characterized by desquamation and erythema. It is thought that patients who experience moderate to severe acute radiation dermatitis and do not receive timely treatment in its early phases are more likely to experience permanent late side effects in the months to years after irradiation, such as fibrosis and capillary dilatation5-7. In regenerative medicine, stem cell therapy has been investigated for the treatment of a number of diseases. Exosome release is one of the paracrine ways that stem cells contribute to their positive effects. A review of the developments in stem cell-derived exosome treatment for RSI was carried out by Kuo et al8. According to the literature review (Table 1), exosomes derived from stem cells have become a new and effective treatment option for RSI. Exosome treatment offers a cell-free method that targets the main pathogenic characteristics of RISI, including fibrosis, dysregulated inflammation, decreased cellular function, and microvascular damage, by concentrating the healing signals of stem cells into small lipid vesicles. Table 1 - Key clinical trials and studies on stem cell-derived exosomes for skin injury Study (year) Condition (injury type) Exosome source (cell type) Delivery method Outcome/Status Rion, 2024 Radiodermatitis (prevention in cancer radiotherapy) Platelet-derived exosomes (purified exosome product, PEP) Topical powder in hydrogel (applied to irradiated skin) Phase I in Progress; no immune reactions observed to date; assessing safety/tolerability in radiation dermatitis patients Traub, 2021 Radiation dermatitis (chronic ulcer postradiotherapy) Mixed skin stem cell secretome (S2RM technology; includes MSC and dermal fibroblast exosomes) Topical gel, applied daily to wound Complete healing of radiotherapy-induced skin lesion in 4 weeks; marked reduction in pain and inflammation Park, 2023 Laser-induced skin injury (ablative fractional laser for acne scars) Adipose-derived MSC exosomes (commercial cosmetic product) Topical, post-laser (splitface study) Significantly improved scar outcomes vs. control; ~13% greater wrinkle reduction; higher skin elasticity; reduced post-procedure redness Rion, 2023 Chronic diabetic foot ulcers (non-radiation chronic wounds) Platelet-derived exosomes (PEP) Topical gel (exosomes mixed in fibrin sealant) Completed Phase II; preliminary reports indicate improved wound closure rates; potentially informative for radiation ulcer approaches NCT05475418, 2022 Chronic cutaneous ulcers (mixed etiologies) ADSC exosomes Topical exosome dressing + hydrogel Recruiting; evaluating safety and efficacy; outcomes include percent wound area reduction and healing time Chen, 2023 Chronic radiation ulcer (rat model) Umbilical cord MSC secretome (exosome-rich CM) Intraperitoneal injections (multiple doses) Significantly slower ulcer progression and enhanced healing; provided rationale for human translation Exosomes are membrane-bound, lipid-bilayered extracellular vesicles that range in size from 50 to 120 nm9. Stem cells use exosomes to interact with non-stem cells and/or each other, much like other bodily cells. Because exosomes from a particular cell type offer distinct sets of soluble secretomes, exosomes may be thought of as miniature replicas of their donor cells. Therefore, comparable therapeutic benefits (such as tissue regeneration and anti-inflammation) are inherited by stem cell-derived exosomes from their parent cell of origin. Unlike stem cells, stem cell-derived exosomes have fewer immunogenic and tumorigenic risks, do not raise any ethical concerns, and may be delivered in a variety of ways (Fig. 1). Unlike cells and conventional medications, exosome therapies provide a unique regulatory category. Small clinical trials have not revealed any serious safety issues, but there are still challenges, such as potential tumor contacts in patients receiving radiation, necessitating localized rather than systemic treatment. Because exosomes are ephemeral and cannot proliferate, long-term impacts are anticipated to be limited, making them potentially safer than cell treatments. Figure 1.: The schematic illustrates the multifaceted protective mechanisms and therapeutic pathways involved in radiation countermeasure strategies. The diagram centers around a bioactive intervention (likely extracellular vesicles or exosomes) containing various bioactive molecules including tetraspanins, integrins, adhesion molecules, lipid rafts, transmembrane proteins, and RNA species that collectively mediate radioprotective effects. Following ionizing radiation exposure (indicated by radiation symbols), the intervention activates six major protective pathways: Antioxidative protection through Nrf2/ARE signaling, which upregulates antioxidant responses and reduces reactive oxygen species (ROS) while mitigating DNA damage and mitochondrial dysfunction; anti-senescence effects via miR-291a-3p and miR-210 targeting TCF-βR2 and HIF-1α, respectively, preventing cellular senescence and promoting tissue regeneration; pro-proliferation and re-epithelialization mechanisms involving miR-135a, miR-126, growth factors (FGF, EGF, PDGF), and Wnt/β-catenin signaling to restore tissue integrity; anti-fibrosis and extracellular matrix remodeling through HGF, microRNA regulation, and TGF-β/SMAD pathway modulation; angiogenesis and vascular protection mediated by VEGF, HGF, and specific microRNAs targeting PI3K/Akt/ERK pathways; and immunomodulation and inflammation resolution through M1-to-M2 macrophage polarization, microRNA-mediated NF-κB suppression, and cytokine balance restoration. This integrated approach demonstrates how targeted therapeutic interventions can simultaneously address multiple radiation-induced pathological processes to enhance survival and tissue recovery. Through “omics” analysis of exosome components, future research seeks to enhance mechanistic knowledge. This information directs augmentation tactics, such as pre-conditioning donor cells to alter exosome composition by exposure to hypoxia or inflammation. For instance, interferon-gamma-γ priming improves angiogenesis in diabetic wounds via increasing mesenchymal stem cell exosomal miR-126-3p. By prestressing cells with radiation, similar methods might produce radiation-specific exosomes. Combination therapies, which may combine exosomes with cellular therapies, growth factors, or conventional wound care treatments, are other potential future directions. In conclusion, overcoming production and regulatory challenges, maximizing transport and dosage, and guaranteeing cost-effectiveness are all critical to the future of stem cell-derived exosome treatment. We expect exosome-based therapies to become more standardized, with a clear composition and solid clinical evidence, as research progresses. This study was conducted in compliance with the Transparency in the Reporting of Artificial Intelligence – the TITAN guideline10.
Weng et al. (Wed,) studied this question.