2f:I[703058,["/_next/static/immutable/chunks/3bhq_5eh1d760.js","/_next/static/immutable/chunks/1855-ogyi8eh4.js","/_next/static/immutable/chunks/2pfsjpn6k6zlg.js","/_next/static/immutable/chunks/26c7v3_3uwnwu.js","/_next/static/immutable/chunks/25a3ozcrvi1ff.js","/_next/static/immutable/chunks/2r4wx50nvjh_4.js","/_next/static/immutable/chunks/23fsw06hsi5b1.js","/_next/static/immutable/chunks/06_yt270h41rg.js","/_next/static/immutable/chunks/3ezsiz-7shkna.js","/_next/static/immutable/chunks/20x2y96ldu5wx.js","/_next/static/immutable/chunks/2lxntcm3pd1_h.js","/_next/static/immutable/chunks/00dgco8irq3jw.js","/_next/static/immutable/chunks/00nwe-kq0rboc.js","/_next/static/immutable/chunks/2051ffx3xzio9.js"],"PaperListPageClient"] 30:Tc1b, Objective This systematic review evaluates the safety, feasibility, tolerability, and efficacy outcomes of intranasally administered stem cells and their derivatives (MSCs, NSCs, secretome, and EVs) for the treatment of neurological and respiratory disorders. Methods A literature search was conducted across PubMed, Google Scholar, Web of Science, Scopus, and ClinicalTrials.gov for published research from January 2011 to December 2025. A total of 19 studies were included (7 published articles, 12 registry-only or grey literature records). Risk of bias was assessed using two complementary Cochrane tools, the RoB 2 tool for all 19 studies and the ROBINS-I tool for the 6 n-RCTs. Sources of heterogeneity were systematically characterized across 5 clinical dimensions, and structural publication bias was evaluated against a 30% registry-only threshold. A random-effects model was selected for pooled analyses, with a planned subgroup analysis of treatment dosage against adverse events. Effect sizes were extracted using SMD, mean differences, risk ratios, and odds ratios as appropriate per outcome type. Results This systematic review was conducted in accordance with PRISMA 2020 guidelines. A total of 104 participants were enrolled in 7 published studies, with one completed registry trial (NCT04602104) confirming actual enrolment of an additional 18 participants. No study achieved an overall low risk of bias under either assessment tool. Under RoB 2, 1 published study was rated as having some concerns, others were rated high risk or some concerns. Under ROBINS-I, 3 n-RCT studies were rated critical overall. The remaining 3 were rated serious. Across the 7 published studies, 98 participants contributed to the analyzed outcomes. Structural publication bias was confirmed. Substantial clinical heterogeneity was identified across 9 conditions, multiple cell product categories, and mixed intranasal and intravenous delivery routes. Conclusion Although current evidence suggests that intranasal administration of stem cells, particularly MSCs and NSCs, in humans is a safe and feasible approach, with possible therapeutic improvements in CNS disorders. However, there is a serious risk of bias, critically small sample sizes, and pervasive publication bias in the available literature. Adequately powered, quadruple-blinded, placebo-controlled randomized trials need to be conducted before clinical translation can be considered. 25:[[["$","script","0",{"type":"application/ld+json","dangerouslySetInnerHTML":{"__html":"{\"@context\":\"https://schema.org\",\"@type\":\"CollectionPage\",\"name\":\"Exosome Therapy: modality Research & Clinical Takeaways\",\"description\":\"Explore peer-reviewed papers on Exosome Therapy (modality). Clinician-written summaries and actionable practice insights. 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results may not generalize to exosomes from normal human liver cells.","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111231","tag_type":"warning","value":"No human subjects were involved; clinical relevance of the liver-eye axis exosome hypothesis remains unestablished.","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111231","tag_type":"warning","value":"Study design classification as 'Preclinical' is used as no standard canonical label covers combined in vitro/in vivo animal research without human subjects.","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111231","tag_type":"warning","value":"The AMD models used (A2E + blue light in ARPE-19 cells and BALB/c mice) simulate only selected AMD features and do not represent the full complexity of human AMD.","value_numeric":null}],"summaries":{"what_studied":"This study examined whether HepG2 hepatocyte-derived exosomes (HG-EX) worsen AMD-like retinal degeneration in A2E-laden ARPE-19 cells exposed to blue light (in vitro) and in blue-light-exposed BALB/c mice (in vivo), focusing on oxidative stress, inflammation, apoptosis, and angiogenesis.","key_result":"HG-EX pretreatment significantly increased intracellular ROS and NO production, suppressed Nrf2 and SOD expression, elevated inflammasome-related and apoptosis-related proteins, and upregulated pro-angiogenic factors in ARPE-19 cells; in mice, HG-EX raised retinal COX-2, TNF-α, IL-1β, IL-6, and Bcl-2/Bax levels while reducing outer segment and inner nuclear layer thickness.","limitations":"- AMD models (A2E + blue light) only approximate selected features of AMD and may not fully recapitulate human disease pathophysiology.\n- HepG2 is a hepatocellular carcinoma cell line; exosomes may not reflect those secreted by normal human hepatocytes.\n- No mechanistic pathway or specific exosomal cargo identified as the driver of retinal damage.","practice_takeaway":"These findings are preclinical and not yet actionable clinically, but they raise the hypothesis that liver-derived exosomes may contribute to AMD pathogenesis via a liver-eye axis, warranting future translational investigation."}},{"doi":"10.1055/a-2905-4174","pmid":"42385784","title":"Regenerative Cell and Cell-Free Therapies for Necrotizing Enterocolitis: Progress Toward Clinical Translation","journal_title":"American Journal of Perinatology","journal_issn":"0735-1631","published_at":"2026-07-07T00:00:00.000Z","url":"https://doi.org/10.1055/a-2905-4174","source_score":4,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-07-09T13:36:05.543Z","updated_at":"2026-07-09T13:36:05.543Z","tags":[{"paper_doi":"10.1055/a-2905-4174","tag_type":"age_group","value":"neonate","value_numeric":null},{"paper_doi":"10.1055/a-2905-4174","tag_type":"category","value":"Obstetrics & Gynecology","value_numeric":null},{"paper_doi":"10.1055/a-2905-4174","tag_type":"condition","value":"Necrotizing Enterocolitis","value_numeric":null},{"paper_doi":"10.1055/a-2905-4174","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1055/a-2905-4174","tag_type":"level_of_evidence","value":"5","value_numeric":null},{"paper_doi":"10.1055/a-2905-4174","tag_type":"modality","value":"Amniotic Fluid Stem Cell Therapy","value_numeric":null},{"paper_doi":"10.1055/a-2905-4174","tag_type":"modality","value":"Exosome Therapy","value_numeric":null},{"paper_doi":"10.1055/a-2905-4174","tag_type":"modality","value":"Extracellular Vesicle Therapy","value_numeric":null},{"paper_doi":"10.1055/a-2905-4174","tag_type":"modality","value":"Mesenchymal Stem Cell Therapy","value_numeric":null},{"paper_doi":"10.1055/a-2905-4174","tag_type":"study_design","value":"Narrative Review","value_numeric":null},{"paper_doi":"10.1055/a-2905-4174","tag_type":"warning","value":"Level of evidence assigned as 5 (expert review/narrative synthesis); individual studies cited within the review may carry higher or lower ratings.","value_numeric":null},{"paper_doi":"10.1055/a-2905-4174","tag_type":"warning","value":"No NEC-specific human trial has been completed; all efficacy conclusions are extrapolated from animal models or adjacent neonatal indications.","value_numeric":null},{"paper_doi":"10.1055/a-2905-4174","tag_type":"warning","value":"No sample size tag applied — this is a narrative review, not a primary study with a discrete patient N.","value_numeric":null},{"paper_doi":"10.1055/a-2905-4174","tag_type":"warning","value":"Sex of subjects not reported; preclinical animal model populations vary across reviewed studies.","value_numeric":null}],"summaries":{"what_studied":"A narrative review synthesizing preclinical, translational, and early-phase clinical trial evidence for stem cell-based (MSCs, AFSCs, placental-derived, neural stem cells) and cell-free extracellular vesicle (EV)/exosome therapies as disease-modifying treatments for necrotizing enterocolitis (NEC) in premature neonates.","key_result":"Multiple stem cell types consistently reduced NEC incidence, severity, and mortality in experimental models via epithelial regeneration, barrier reinforcement, Wnt/β-catenin activation, immunomodulation, and angiogenesis. MSC- and AFSC-derived EVs replicated these benefits with a more favorable manufacturing and safety profile. Early-phase MSC trials in other neonatal conditions confirmed short-term tolerability, but no completed NEC-specific stem cell or EV trial exists.","limitations":"- All efficacy data are from preclinical (animal) models; no completed NEC-specific human trial exists.\n- Narrative review design is inherently subject to selection bias.\n- Lack of standardized cell/EV characterization and dosing protocols across studies limits comparability.","practice_takeaway":"No stem cell or EV therapy for NEC is ready for routine clinical use; current evidence is preclinical only. Clinicians should watch for early-phase NEC-specific trials, as this class of therapies shows consistent promise in animal models and tolerability signals in adjacent neonatal indications."}},{"doi":"10.1016/j.exer.2026.111049","pmid":"42119839","title":"Limbal niche cell-derived exosomes accelerate corneal epithelial repair through PI3K/Akt activation and FOXO3 inhibition","journal_title":"Experimental Eye Research","journal_issn":"0014-4835","published_at":"2026-05-12T00:00:00.000Z","url":"https://doi.org/10.1016/j.exer.2026.111049","source_score":3,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-05-13T13:19:23.705Z","updated_at":"2026-05-13T13:19:23.705Z","tags":[{"paper_doi":"10.1016/j.exer.2026.111049","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111049","tag_type":"brand","value":"LY294002","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111049","tag_type":"category","value":"Ophthalmology","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111049","tag_type":"condition","value":"Corneal Epithelial Defects","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111049","tag_type":"generic","value":"limbal niche cell-derived exosomes","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111049","tag_type":"generic","value":"recombinant human basic fibroblast growth factor","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111049","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111049","tag_type":"level_of_evidence","value":"6","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111049","tag_type":"modality","value":"Cell-Free Regenerative Medicine","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111049","tag_type":"modality","value":"Exosome Therapy","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111049","tag_type":"study_design","value":"Preclinical In Vitro and In Vivo Study","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111049","tag_type":"warning","value":"LY294002 is listed as a research tool/inhibitor, not a clinical drug — tagged under generic rather than brand to avoid confusion.","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111049","tag_type":"warning","value":"No sample size (N) is reported in the abstract for in vitro or in vivo experiments; sample_size tag omitted.","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111049","tag_type":"warning","value":"Paper published 2026-05-12 — only one day before today's date; findings are very recent and not yet peer-reviewed or replicated externally.","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111049","tag_type":"warning","value":"Study design label is non-standard (combined in vitro/in vivo preclinical); no randomized clinical component is present.","value_numeric":null}],"summaries":{"what_studied":"Exosomes derived from human limbal niche cells (LNC-exo) were evaluated for their ability to promote corneal epithelial wound healing — in vitro using immortalized human corneal epithelial cells (HCE-T), and in vivo in a mouse corneal epithelial defect model — with mechanistic focus on the PI3K/Akt/FOXO3 signaling axis.","key_result":"LNC-exo dose-dependently increased proliferation and migration of HCE-T cells via PI3K/Akt activation and FOXO3 suppression (blocked by PI3K inhibitor LY294002); in the mouse model, topical LNC-exo accelerated wound closure at an efficacy comparable to recombinant human basic fibroblast growth factor (rh-bFGF).","limitations":"Study relies on an immortalized cell line (HCE-T) rather than primary corneal epithelial cells; the in vivo model is murine, limiting direct translation to human disease; no long-term safety, dosing, or pharmacokinetic data are provided.","practice_takeaway":"LNC-exo are not yet clinically available, but these preclinical findings position them as a potential cell-free topical agent for corneal epithelial defects — a gap that current therapies inadequately address. Clinicians should watch for early-phase trials translating this approach."}},{"doi":"10.3389/fnagi.2026.1834543","pmid":null,"title":"Intranasal administration of stem cells and their derivatives for neurological and respiratory disorders: a systematic review of human clinical trials","journal_title":"Frontiers in Aging Neuroscience","journal_issn":"1663-4365","published_at":"2026-05-07T00:00:00.000Z","url":"https://doi.org/10.3389/fnagi.2026.1834543","source_score":184,"is_retracted":false,"is_open_access":true,"raw_metadata":{"ooir":{"day":"2026-05-10","doi":"10.3389/fnagi.2026.1834543","days":"7","issn":"1663-4365","rank":"2","field":"Clinical Medicine","score":"184","category":"Neurosciences","categories":["Neurosciences"],"_categories":["Neurosciences"]},"pubmed":null,"crossref":{"DOI":"10.3389/fnagi.2026.1834543","URL":"https://doi.org/10.3389/fnagi.2026.1834543","ISSN":["1663-4365"],"link":[{"URL":"https://www.frontiersin.org/articles/10.3389/fnagi.2026.1834543/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"page":null,"type":"journal-article","issue":null,"score":1,"title":["Intranasal administration of stem cells and their derivatives for neurological and respiratory disorders: a systematic review of human clinical trials"],"author":[{"given":"Umm E.","family":"Habiba","sequence":"first","affiliation":[{"name":"Research and Development (R&D) Department, R3 Stem Cell LLC"},{"name":"Research and Development (R&D) Department, R3 Medical Research LLC"}]},{"given":"Roshini","family":"Sathyanarayanan","sequence":"additional","affiliation":[{"name":"Research and Development (R&D) Department, R3 Medical Research LLC"}]},{"given":"Sabiha","family":"Shamim","sequence":"additional","affiliation":[{"name":"Research and Development (R&D) Department, R3 Medical Research LLC"}]},{"given":"Aishwarya","family":"Manian","sequence":"additional","affiliation":[{"name":"Research and Development (R&D) Department, R3 Medical Research LLC"}]},{"given":"Ammar","family":"Haider","sequence":"additional","affiliation":[{"name":"Research and Development (R&D) Department, R3 Medical Research LLC"}]},{"given":"Iqra","family":"Sarwar","sequence":"additional","affiliation":[{"name":"Research and Development (R&D) Department, R3 Medical Research LLC"}]},{"given":"David Lawrence","family":"Greene","sequence":"additional","affiliation":[{"name":"Research and Development (R&D) Department, R3 Stem Cell LLC"},{"name":"Research and Development (R&D) Department, R3 Medical Research LLC"}]}],"issued":{"date-parts":[[2026,5,7]]},"member":"1965","prefix":"10.3389","source":"Crossref","volume":"18","created":{"date-time":"2026-05-07T05:41:35Z","timestamp":1778132495000,"date-parts":[[2026,5,7]]},"indexed":{"date-time":"2026-05-07T06:14:44Z","timestamp":1778134484033,"date-parts":[[2026,5,7]]},"license":[{"URL":"https://creativecommons.org/licenses/by/4.0/","start":{"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000,"date-parts":[[2026,5,7]]},"delay-in-days":0,"content-version":"vor"}],"subject":[],"abstract":"$30","relation":{},"resource":{"primary":{"URL":"https://www.frontiersin.org/articles/10.3389/fnagi.2026.1834543/full"}},"subtitle":[],"deposited":{"date-time":"2026-05-07T05:41:36Z","timestamp":1778132496000,"date-parts":[[2026,5,7]]},"issn-type":[{"type":"electronic","value":"1663-4365"}],"published":{"date-parts":[[2026,5,7]]},"publisher":"Frontiers Media SA","reference":[{"DOI":"10.1186/s13287-025-04254-0","key":"ref1","year":"2025","issue":null,"author":"Allouh","volume":"16","first-page":"127","unstructured":null,"article-title":"Mesenchymal stromal/stem cells from perinatal sources: biological facts, molecular biomarkers, and therapeutic promises","journal-title":"Stem Cell Res Ther","doi-asserted-by":"publisher"},{"DOI":"10.3390/pharmaceutics14020381","key":"ref2","year":"2022","issue":null,"author":"Alvites","volume":"14","first-page":"381","unstructured":null,"article-title":"Mesenchymal stem/stromal cells and their paracrine activity—immunomodulation mechanisms and how to influence the therapeutic potential","journal-title":"Pharmaceutics","doi-asserted-by":"publisher"},{"DOI":"10.25259/SNI_233_2020","key":"ref3","year":"2020","issue":null,"author":"Boika","volume":"11","first-page":"380","unstructured":null,"article-title":"Mesenchymal stem cells in Parkinson’s disease: motor and nonmotor symptoms in the early posttransplant period","journal-title":"Surg. 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Structural publication bias was confirmed (63% registry-only or grey literature, exceeding the 30% threshold). Across 98 analyzed participants from 7 published studies, intranasal delivery was consistently reported as safe with no serious adverse events, and preliminary signals of benefit appeared in cerebral palsy, perinatal stroke, and Alzheimer's disease — but no efficacy conclusion is interpretable due to open-label design, absent sham controls, and unblinded outcome assessment in every published trial.","limitations":"- Every published study lacked randomization, sham/placebo intranasal control, and blinded outcome assessment, making efficacy estimates uninterpretable as biological activity.\n- Multiple studies combined intranasal and intravenous delivery, preventing route-specific attribution of any observed effect.\n- The review itself was not pre-registered in PROSPERO, and several authors have direct conflicts of interest (employment by the stem cell manufacturer whose products were evaluated).","practice_takeaway":"Do not adopt intranasal stem cell or exosome therapy for any neurological or respiratory condition based on current evidence — no adequately powered, blinded, sham-controlled trial has been completed or published. The safety signal across ~98 participants is reassuring enough to justify rigorously designed Phase 2 trials, but not clinical use."}}],"initialOffset":4,"fetchConfig":{"kind":"tags","tags":[{"tag_type":"modality","value":"Exosome Therapy"}]},"breadcrumbItems":[{"name":"Home","href":"/"},{"name":"Research Hub","href":"/hub"},{"name":"Modalities","href":"/hub/tag/modality"},{"name":"Exosome Therapy"}],"hrefConfig":{"basePath":"/hub/papers","webViewQueryParams":{"hub_ctx":"tag","hub_tag_type":"modality","hub_tag_value":"Exosome Therapy"}}}]]

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