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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.
Habiba et al. (Thu,) studied this question.