Intranasal delivery of regenerative biologics for neurological disorders: a systematic review of clinical studies.

INTRODUCTION: Intranasal delivery is a minimally invasive route for administering regenerative biologics to the central nervous system while bypassing the blood-brain barrier. Human clinical evidence for this approach across neurological disorders remains dispersed across multiple disease areas, biologic classes, dosing frameworks, and delivery methods, limiting field-level synthesis. This study was conducted to systematically evaluate the safety, dosing characteristics, delivery method heterogeneity, and disease-specific direction of effect of intranasal regenerative biologics, including mesenchymal stromal cells (MSCs), neural stem cells (NSCs), exosomes, secretome and conditioned medium, breast milk-derived biologic preparations, and related regenerative products, in patients with neurological disorders. METHODOLOGY: An International Prospective Register of Systematic Reviews (PROSPERO)-registered systematic review was conducted and reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines, with synthesis performed in accordance with Synthesis Without Meta-Analysis (SWiM) recommendations. PubMed, Google Scholar, ClinicalTrials.gov, and ChiCTR were searched from January 2015 to August 2026. Risk of Bias (RoB) was assessed using study design-appropriate validated tools, including Cochrane RoB 2 and Risk of Bias In Non-randomized Studies - of Interventions (ROBINS-I) and methodological quality of uncontrolled studies was appraised using the Joanna Briggs Institute (JBI) Critical Appraisal Checklists for Case Series and Case Reports. RESULTS: Sixteen publications comprising 18 patient cohorts across 12 neurological conditions were included. No treatment-related serious adverse events were reported. Most cohorts showed clinical improvement, while one reported stabilization, though the predominantly uncontrolled designs mean placebo response and natural disease history cannot be ruled out. However, the biologic class was strongly confounded by disease indication, dosing was heterogeneous and non-comparable, and five delivery techniques were used. DISCUSSION: By integrating clinical evidence across biologic classes and neurological disorders, this review defines the current safety landscape, highlights major methodological gaps, and provides a framework for standardized future intranasal regenerative trials. CONCLUSION: Adequately powered, standardized, and controlled trials are required before clinical adoption can be considered.