---
title: "Non-human-derived exosomes as a potential therapy for periodontitis"
id: "frontiers-in-immunology-8-gift-of-nature-non-human-derived-exosomes-showing-application-prospects-in"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-8-gift-of-nature-non-human-derived-exosomes-showing-application-prospects-in"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1814654"
published_at: "2026-09-02T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Non-human-derived exosomes as a potential therapy for periodontitis
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-8-gift-of-nature-non-human-derived-exosomes-showing-application-prospects-in
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1814654)
- **Published At:** 2026-09-02T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The source article title indicates interest in the application prospects of **non-human-derived exosomes** for treating **periodontitis**. - The provided SOURCE JINA BODY contains only website navigation, repeated journal front matter, and no article content or abstract. - No experimental data, methods, results, or author conclusions from the article were available in the provided source text. - The source did not report specifics on exosome origin (which non-human species or cell types), isolation methods, cargo characterization, delivery routes, dosing, in vitro or in vivo findings, safety, or regulatory considerations. - The source did not report any comparative analyses between non-human-derived exosomes and human-derived exosomes or other periodontal therapies. - The source did not provide timelines for clinical translation, suggested mechanisms of action, or references to supportive preclinical or clinical evidence. - Because full article content was not present in the supplied source, any further details such as study design, outcomes, limitations, or authors’ recommendations were not reported and cannot be inferred from the provided text. - For clinicians and researchers seeking actionable information, the actual article PDF or full-text page on Frontiers in Immunology must be consulted; the supplied source is insufficient to support clinical or research conclusions about **non-human-derived exosomes** in **periodontitis**.
## Clinical Analysis & Structured Key Points
Frontiers | Gift of nature: non-human-derived exosomes showing application prospects in periodontitis treatment REVIEW article Front. Immunol. , 02 September 2026 Sec. Inflammation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1814654 Published in Frontiers in Immunology Inflammation 7 impact factor 11.3 citescore Part of a Research Topic The Role of Extracellular Vesicles in Advanced Drug and Vaccine Delivery Submission open 74k views 12 articles Editor & Reviewers Edited by R R Roopali Rajput Reviewed by Q M Qiong Meng N R Nisha Rathor Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Table 1 Summary of studies on the anti-inflammatory effects of non-human-derived exosomes over the last 5 years. View in article Table 2 Summary of studies showing the immune-modulatory effects of non-human-derived exosomes over the last 5 years. View in article Table 3 Summary of studies showing the tissue-regenerative effects of non-human-derived exosomes over the last 5 years. View in article Table 4 Summary of studies on the angiogenic effects of non-human-derived exosomes over the last 5 years. View in article Table 5 Clinical trials of exosome treatment for inflammatory diseases over the last 5 years. View in article REVIEW article Front. Immunol. , 02 September 2026 Sec. Inflammation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1814654 Gift of nature: non-human-derived exosomes showing application prospects in periodontitis treatment H F Hongbo Fei 1,2 † Z W Zhuoran Wang 3 † Y L Yujiao Li 1 H S Hongchen Sun 1,2 * X M Xiuping Meng 1 * H L Hongbing Lin 1,2 * 1. Hospital of Stomatology, Jilin University, Changchun, China 2. Jilin Provincial Key Laboratory of Oral and Craniofacial Diseases & Tissue Reconstruction, Jilin University, Changchun, China 3. Department of Periodontology, College of Stomatology, Xi’an Jiaotong University, Xi’an, China See more Article metrics View details Abstract Periodontitis, a chronic inflammatory disorder, results in tooth loss and adversely affects oral and systemic health. Current therapies fail to effectively regenerate bone loss caused by inflammation. Human stem cell-derived exosomes have emerged as important mediators of tissue regeneration and inflammation modulation in periodontitis, yet their clinical use faces ethical and technical challenges. Non-human-derived exosomes present a viable alternative, leveraging their ability to enhance tissue repair, reduce inflammation, and stimulate regeneration. This review synthesizes recent advances (2020–2025) in non-human-derived exosome applications, emphasizing their roles in immunomodulation, angiogenesis, and periodontal regeneration, while evaluating clinical translation prospects. Graphical Abstract Therapeutic effects of non-human-derived exosomes and their potential as a therapeutic approach for periodontitis. Non-human-derived exosomes (PELNs, ADEs, and their engineered derivatives) have demonstrated anti-inflammatory, immune-modulatory, tissue-regenerative, and angiogenic effects that play a key role in periodontitis treatment. 1 Introduction Periodontitis, marked by progressive destruction of periodontal structures, is a global health burden linked to systemic conditions like diabetes and cardiovascular diseases ( 1 , 2 ). The Fourth National Oral Health Survey shows that about 62.3% of adults aged 35 and above in China suffer from varying degrees of periodontitis, and the severity is positively correlated with age ( 3 ). At present, non-surgical and surgical methods are commonly used, combined with various biomaterials and biological media to reconstruct damaged periodontal tissue, thereby improving the prognosis and quality of life of patients. However, the effects are limited ( 4 , 5 ). Recent studies of cellular communication have highlighted the role of exosomes in mediating tissue regeneration and modulating inflammatory responses associated with periodontitis. Exosomes are nano-sized vesicles secreted from various cells that facilitate intercellular communication and influence the behavior of recipient cells ( 6 ). Their unique characteristics, such as low immunogenicity, biocompatibility, and delivery capacity, make them promising candidates for therapeutic applications ( 7 ). Exosomes derived from mesenchymal stem cells (MSCs) have been shown to enhance periodontal regeneration ( 8 ). Exosome-based strategies have highlighted the potential to promote periodontal regeneration through regulation of immune cells and stem cells ( 6 ). Although exosomes derived from humans have shown promise in periodontal treatment, their clinical application is constrained by several major issues, including (1) the difficulty of obtaining human MSCs and associated ethical issues; (2) low production yields; and (3) the time-consuming and laborious production process ( 9 , 10 ). Exosomes derived from non-humans offer an intriguing substitute. They come from a wide range of sources and have similar or even higher biocompatibility. Notably, their therapeutic value lies in their capacity to improve tissue healing, diminish inflammation, and promote tissue regeneration, which positions them as viable choices for novel treatments of periodontitis ( 9 ). However, a vast majority of current systematic reviews remain focused on human-derived exosomes, while systematic reviews centered on non-human-derived exosomes remain scarce. To address this research gap, the present review focuses exclusively on non-human-derived exosomes and systematically consolidates the latest research advancements from the last 5 years, covering exosomes from animal, plant, and engineered sources. This work comprehensively integrates their underlying mechanisms in regulating inflammation, immune responses, angiogenesis, and periodontal tissue regeneration, while critically discussing the limitations of cross-disease extrapolation and the core challenges hindering clinical translation. By highlighting the unique therapeutic properties of non-human-derived exosomes in periodontitis therapy, this review aims to provide a comprehensive and innovative perspective to enrich the current body of relevant literature. 2 Sources and application of non-human-derived exosomes Accumulating evidence demonstrates that plant-derived exosome-like nanovesicles share highly similar biogenesis pathways with mammalian-derived exosomes, mainly through the multivesicular bodies (MVBs) pathway ( 11 ). To accurately reflect the specific nomenclature of the original cited studies, we utilized terms such as ‘exosomes’, ‘exosome-like nanoparticles’, or ‘nanovesicles’ throughout this manuscript, which collectively fall under the broader, standardized umbrella of non-human-derived exosomes. Similar to exosomes derived from humans, non-human-derived exosomes are classified based on their origin, including animal, plant, and engineered sources, and also play a crucial role in intercellular communication. 2.1 Animal-derived exosomes Human-derived exosomes have been extensively studied for their therapeutic potential. For instance, exosomes derived from MSCs show promise in numerous medical applications, including neuroprotection and tissue repair ( 12 ). However, ethical issues and difficulties in isolation constrain the clinical application of exosomes derived from human MSCs. Plantz et al. demonstrated the abundance of exosomes in bovine milk and their role in treating diseases ( 13 ). Therefore, animal-derived exosomes (ADEs) from various sources were subsequently identified and shown to promote treatments in both humans and animals ( 14 , 15 ). 2.2 Plant-derived exosome-like nanoparticles Plant-derived exosome-like nanoparticles (PELNs; 50–500 nm) are enriched with lipids like phosphatidic acid, facilitating cross-species communication ( 16 ). Derived from fruits, vegetables, and herbs, PELNs are cost-effective and scalable and exhibit low immunogenicity ( 11 ). In addition, their potential for large-scale production gives PELNs great potential for application ( 9 ). 2.3 Engineered exosomes Surface modification and cargo loading [e.g., drugs and microRNAs (miRNAs)] enhance exosome targeting and therapeutic efficacy ( 9 ). Techniques like membrane hybridization and 3D-printed scaffolds optimize delivery for periodontal applications ( 17 ). For instance, engineered exosomes represent a novel approach in the field of drug delivery, where exosomes are modified to enhance their therapeutic efficacy ( 18 ). Non-human-derived exosomes from different sources exhibit distinct therapeutic merits and limitations. ADEs, especially those isolated from milk, feature high yields, favorable cost efficiency, and superior biocompatibility, whereas they are associated with potential risks, including batch-to-batch inconsistency and cross-species viral transmission ( 19 ). PELNs support large-scale production and possess low intrinsic immunogenicity with proven dietary safety ( 9 ). Nevertheless, high-purity extraction and the standardization of cross-kingdom communication mechanisms remain major challenges ( 20 ). Engineered exosomes enable precise targeting and optimized cargo delivery; still, key challenges in engineered exosome translational research center on the lack of standardized protocols for isolation and clinical quantification, and the optimization of exosome source selection to match specific functional requirements ( 21 ). 3 Extraction and purification techniques Ultracentrifugation, size-exclusion chromatography, and commercial isolation kits are the most common methods for exosome extraction. Ultracentrifugation is the traditional gold standard, providing high yields but requiring significant time and expertise ( 22 ). However, ultracentrifugation can lead to co-isolation of proteins and other contaminants, affecting the purity of the final exosome preparation ( 23 ). Size-exclusion chromatography offers a gentler approach that not only preserves the integrity of exosomes but also effectively separates them from contaminants. Furthermore, size-exclusion chromatography tends to yield purer exosome fractions but may result in lower overall yields ( 24 ). Commercial kits offer convenience and user-friendliness but are costly and may not always provide the highest purity. 4 The potential role of non-human-derived exosomes in periodontitis therapy Periodontal tissue has a complex composition, which presents challenges for tissue engineering strategies ( 25 ). Anti-inflammatory activity, immune regulation, tissue regeneration, and angiogenesis are key components of periodontal tissue engineering. Literature reports reveal various biological activities of extracellular vesicles from non-human sources. These biological activities can promote periodontal tissue regeneration ( Figure 1 ). Figure 1 Biological activities of non-human-derived exosomes that may facilitate periodontal regeneration. Created with Biorender.com . 4.1 Anti-inflammatory effects Traditional treatment methods for periodontitis, which focus on eliminating pathogenic microorganisms and using adjunctive pharmacotherapy, may result in resistance and increased rates of recurrence ( 26 ). In recent decades, people have attached increasing importance to using natural foods to treat human diseases. Xie et al. demonstrated that ginseng-derived exosome-like nanoparticles (GELNs) mainly alleviate inflammatory responses by suppressing the nuclear factor kappa B (NF-κB) signaling pathway ( 27 ). In addition, Yin et al. investigated the anti-inflammatory effects of GELNs. The results demonstrated that GELNs may counteract inflammation induced by lipopolysaccharide through miRNAs enriched in GELNs ( 28 ). Animal-derived exosomes are a natural nutrient. Lu et al. showed that sheep milk-derived exosomes (sheep MDEs) may reduce interleukin-6 (IL-6) and interleukin-12 (IL-12) production by suppressing the toll-like receptor 4 (TLR4)/TRAF1-IκBα-p65 pathway through miRNAs ( 14 ). Chen et al. reported that vesicle-like nanoparticles in honey (H-VLNs) may impede the formation and activation of the pyrin domain-containing 3 (NLRP3) inflammasome through miR-4057 ( 29 ). Luteolin (Lu) has notable bioactive properties, but its effects are hindered by water solubility and bioavailability. To overcome these disadvantages, Jiang et al. encapsulated Lu in sesame leaf-derived exosome-like nanovesicles (Exo@Lu) and demonstrated that Exo@Lu may improve the reduction in pro-inflammatory cytokines compared with free Lu ( 30 ). Detailed information on the anti-inflammatory effects of non-human-derived exosomes is listed in Table 1 . Table 1 Name Source NTA (nm) Anti-inflammatory effects Ref. sheep MDEs Sheep milk 87.95 ± 19.26 To reduce IL-6 and IL-12 production by suppressing the TLR4/TRAF1-IκBα-p65 pathway through miRNAs. ( 14 ) GELNs Ginger ~161.2 To regulate oxidative stress and inflammatory reactions by inhibiting the NF-κB pathway. ( 27 ) GELNs Ginger 156 ± 36 To downregulate inflammation through miRNAs. ( 28 ) H-VLNs Honey 120–180 To impede the formation and activation of the NLRP3 inflammasome through miR-4057. ( 29 ) Exo@Lu Lycium barbarum L. 151.45 ± 3.86 To reduce pro-inflammatory cytokine expression compared with free Lu. ( 30 ) Summary of studies on the anti-inflammatory effects of non-human-derived exosomes over the last 5 years. 4.2 Immune modulation The immunomodulatory properties of non-human-derived exosomes extend beyond mere anti-inflammatory effects. These exosomes can influence immune cell behavior and enhance the overall immune response to periodontal pathogens ( Figure 2 ). Figure 2 The immune-modulatory effects of non-human-derived exosomes. (A) The effect of non-human-derived exosomes on macrophage modulation. (a) Schematic diagram of GelMA/DAS/Exo modulation of macrophage polarization; (b, c) . Gene expression of cytokines; (d–f) . The fluorescence intensity of Arg-1 and iNOS. (g, h) . Protein expression of Arg-1 and iNOS; (i) The proportions of M1 and M2 macrophages. Reproduced with permission ( 35 ). (B) The effect of non-human-derived exosomes on T-cell modulation. (a, b) . Flow cytometric analysis of T cells in spleens from psoriasis. Reproduced with permission ( 39 ) * p <0.05; ** p <0.01; *** p <0.001. The role of non-human-derived exosomes in modulating macrophages has been studied most extensively. First, non-human-derived exosomes may inhibit macrophage infiltration or recruitment. Zhang et al. demonstrated that exosomes derived from deer antler stem cells (AnSC-Exos) may inhibit circulating macrophage recruitment by inhibiting C-C motif chemokine ligand 7 (CCL7) expression in fibroblasts ( 31 ). Zhao et al. showed that garlic-derived exosome-like nanovesicles (GaELNVs) may ameliorate inflammatory eruptions by downregulating pro-inflammatory cytokine expression in the serum and hinder macrophage infiltration by inhibiting C-C motif chemokine receptor 2 (CCR2)/C-C motif chemokine receptor 5 (CCR5) signaling ( 32 ). Kim et al. showed that nanosized ginseng-derived exosome-like nanoparticles (GENs) exhibited strong efficacy in recruiting M1 macrophages ( 33 ). Second, non-human-derived exosomes play an important role in regulating macrophage polarization. Ou et al. showed that Catharanthus roseus (L.) Don leaf-derived exosome-like nanovesicles (CLDENs) may target immune organs, promote macrophage polarization, and promote lymphocyte proliferation in vitro ( 34 ). Lemon exosomes may regulate macrophage polarization, although limitations in drug delivery and penetration depth need to be addressed. Jin et al. loaded lemon exosomes into gelatin methacryloyl and dialdehyde starch to produce a GelMA-DAS-Lemon Exosomes hydrogel (GelMA/DAS/Exo hydrogel) and effectively promote the sustained release of exosomes ( 35 ). RAW264.7 macrophages were co-cultured with the GelMA/DAS/Exo hydrogel ( Figure 2(A)a) . After 24 hours, expression of the M1-associated markers inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-α) was downregulated in both the Lemon Exosomes and GelMA/DAS/Exo groups, whereas the M2-associated markers arginase-1 (Arg-1) and interleukin-10 (IL-10) were upregulated ( Figures 2(A)b, c ). To recapitulate the inflammatory conditions characteristic of diabetic wounds, RAW264.7 cells were pre-stimulated with lipopolysaccharide (LPS) before hydrogel treatment. Immunofluorescence and Western blot analyses showed that exposure to either lemon exosomes or the GelMA/DAS/Exo hydrogel reduced the proportion of iNOS-positive M1 macrophages and increased that of Arg-1-positive M2 macrophages ( Figures 2(A)d–h ). These findings were further corroborated by flow cytometry, which revealed a decrease in CD86 + cells from 13.3% to 2.05% and an increase in CD206 + cells from 12.9% to 61.4% ( Figure 2(A)i . Third, non-human-derived exosomes may regulate molecule expression. Martínez Fajardo et al. showed that exosomes derived from saffron tepals selectively stimulate macrophages and may increase CD80 and CD86 expression ( 36 ). Astaxanthin (AST) has excellent anti-inflammatory activity, but its limited biocompatibility restricts its applications. To overcome the disadvantages of AST, Cui et al. constructed hyaluronic acid-modified milk exosome-based astaxanthin (HA-mExo). The delivery system may accumulate in macrophages and significantly inhibit the expression of pro-inflammatory factors ( 37 ). In addition, non-human-derived exosomes have also been reported to modulate T cells. Zhu et al. showed that Portulaca oleracea L.-derived exosome-like nanoparticles (PELNs) may activate the aryl hydrocarbon receptor on the surface of CD4+ T cells and reprogram T cells into double-positive CD4 + CD8 + T cells ( 38 ). To improve efficacy in reaching the target tissue, Huang et al. encapsulated CX5461 in grapefruit-derived exosome-like nanovesicles (GEVs), which were then fused with engineered gingiva-derived MSCs to produce FV@CX5461. FV@CX5461 may reshape the unbalanced immune microenvironment by reducing inflammatory factor expression, downregulating Th17 activation, and promoting Treg infiltration ( 39 ). Flow cytometry confirmed the therapeutic effect of FV@CX5461. Compared with the other groups, FV@CX5461 markedly reduced both the absolute count of CD3 + T cells and the percentage of CD4 + T cells. It also decreased the proportion of splenic Th17 cells while increasing the frequency of CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) ( Figures 2(B)a, b ). Detailed information on the immune-modulatory effects of non-human-derived exosomes is listed in Table 2 . Table 2 Name Source NTA (nm) Immune modulation Ref. AnSC-Exos deer antler 120 To inhibit macrophage recruitment by inhibiting CCL7 expression in fibroblasts. ( 31 ) GaELNVs Garlic 43.82–396.1 To hinder macrophage infiltration by inhibiting CCR2/CCR5 signaling ( 32 ) GENs Ginseng 151.6 To recruit M1 macrophages. ( 33 ) CLDENs Catharanthus roseus 75.51 ± 10.19 To enhance macrophage polarization and lymphocyte proliferation. ( 34 ) GelMA/DAS/Exo hydrogel Lemon 85–515 To regulate the polarization reprogramming of macrophages. ( 35 ) Exosomes derived from Saffron tepals Saffron tepals 151.5 ± 79.6 To increase the expression of surface molecules on macrophages. ( 36 ) HA-mExo Milk 100 To accumulate in macrophages and inhibit the expression of inflammatory factors. ( 37 ) PELNs Portulaca oleracea L ~ 160 To reprogram CD4+ T cells into CD4 + CD8 + T cells. ( 38 ) FV@CX5461 Grapefruit 163.4 To downregulate Th17 activation and promote Treg infiltration. ( 39 ) Summary of studies showing the immune-modulatory effects of non-human-derived exosomes over the last 5 years. 4.3 Tissue regeneration Non-human-derived exosomes, rich in growth factors and bioactive molecules, facilitate cellular processes essential for tissue regeneration. Recently, numerous studies on non-human-derived exosomes have demonstrated tissue-regenerative e
## Related Clinical Research

- [Health and Economic Impact of Scaling Monthly Oral PrEP (MK-8527) Versus Injectable Lenacapavir in](https://medichelpline.com/clinical-feed/medrxiv-10-modeling-the-health-and-economic-impact-of-scaling-up-monthly-oral-pre-exposure.md)
- [Household transmission of Shigella vs Campylobacter: paired cohorts in Bangladesh and Tanzania](https://medichelpline.com/clinical-feed/medrxiv-8-comparative-analysis-of-shigella-and-campylobacter-transmission-in-paired.md)
- [Fauci on pandemic memory: selective amnesia and its effect on views of masking and lockdowns](https://medichelpline.com/clinical-feed/stat-news-1-stat-fauci-speaks-and-writes.md)
- [Lysine acylation and its potential role in metabolic and inflammatory processes in MASLD](https://medichelpline.com/clinical-feed/frontiers-in-immunology-19-the-role-of-lysine-acylation-in-metabolic-dysregulation-and-inflammatory.md)
- [Medical groups, Vaccine Integrity Project issue joint RSV, Covid-19, and influenza vaccine guidanc](https://medichelpline.com/clinical-feed/stat-news-0-doctors-groups-release-vaccination-guidelines-ahead-of-respiratory-illness.md)

## Navigation
- [← Back to Infectious Disease Feed](https://medichelpline.com/clinical-feed/infectious-disease.md)
- [← All Clinical Specialties](https://medichelpline.com/clinical-feed.md)
## Medical & Regulatory Disclaimer

> [!CAUTION]
> MedicHelpline content is structured for research, educational, and professional discovery purposes. It does not constitute individual medical advice, clinical diagnosis, or treatment recommendations.
> Always verify dosing, contraindications, and regulatory alerts against official product labeling and primary regulatory sources before clinical decision-making.