Cell-based and bioengineered transplantation strategies for neurodegenerative diseases: a systematic review of mechanisms, clinical outcomes, and translational barriers

Neurodegenerative disorders like Alzheimer’s disease (AD) are characterized by progressive loss of neurons, and few therapeutic options are available to restore damaged neural function. Experimental models have shown promising proof of the regenerative capabilities of cell-based and bioengineered transplantation methods, such as stem cells, EVs, organoids, and biomaterial-assisted transplantation. There are, however, significant hurdles to be overcome in translating these results to create lasting clinical improvements. This systematic review was designed to critically summarize available evidence for cell-based and bioengineered transplantation strategies for AD while focusing on therapeutic mechanisms, preclinical and clinical results, and obstacles to clinical translation. The review followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA 2020) guideline. Studies related to the topic were searched from January 2015 to December 2025 using PubMed, Scopus, and Web of Science. The following studies were examined: stem cell therapy, extracellular vesicle treatment, neural tissue engineering, and organoids/bioengineered constructs. After screening and determining eligibility, 30 studies were finally synthesized. The evidence was analyzed narratively and comparatively, as results were statistically heterogeneous with regard to study design, disease model, intervention, and measures of outcomes. The studies included in this review showed promising preclinical efficacy associated with various therapeutic approaches with regard to neuroprotective, immunomodulating, neuronal survival, regenerative signaling, and tissue-supporting outcomes. The available evidence base, however, is from a predominantly preclinical source, and the conclusions that can be drawn on long-term clinical effectiveness are therefore limited. Hostile neurodegenerative microenvironments, restricted graft survival or integration of synapses, limitations of biomaterial compatibility and degradation, delivery constraints, blood-brain barrier limitations, safety concerns, timing of intervention, and regulatory and manufacturing challenges were important translation barriers. The synthesis was followed by the creation of a Three-Node Translational Gap Framework that includes interconnected biological, biomaterial, and clinical elements that could collectively account for the gap between experiments and clinical translation. Cell-based and bioengineered transplantation strategies are very promising in the experimental field, but their efficiency in AD has not been demonstrated. Optimization of biological compatibility, biomaterial performance, delivery, safety, patient selection, and clinical implementation are to be optimized simultaneously for future translation. Although it remains not fully understood, standardized biomarkers, well- powered, well-designed, longitudinal clinical trials, and integrated multimodal approaches can help link therapeutic effects at the cellular level to actual functional outcomes.