Why does siRNA delivery still fail in neurodegenerative diseases? Biological barriers, nanocarrier engineering, and future translational directions.

Neurodegenerative diseases remain largely untreatable at the disease-modifying level, with currently approved therapies providing primarily symptomatic benefits. Small interfering RNA (siRNA) has emerged as a promising therapeutic modality because of its ability to selectively silence disease-associated genes. However, a major obstacle to clinical translation is not the gene-silencing mechanism itself, but the efficient delivery of therapeutic siRNAs to target cells within the central nervous system.This review examines the barriers that limit siRNA-based therapies for neurodegenerative diseases. We adopt a barrier-oriented framework that follows the sequential challenges encountered during siRNA delivery, including extracellular instability, unfavorable pharmacokinetics, immune recognition, limited transport across the blood-brain barrier, inefficient cellular internalization, and endosomal entrapment. Rather than cataloguing available delivery systems, we evaluate how nanocarrier engineering strategies have been developed to address these barriers and assess their impact on delivery. Evidence from Alzheimer's disease, Parkinson's disease, and Huntington's disease is synthesized to distinguish shared limitations from disease-specific challenges and to evaluate the translational performance of lipid-based nanoparticles, polymeric nanocarriers, engineered exosomes, and hybrid platforms.Available evidence indicates that delivery platforms can improve specific aspects of siRNA transport but have not consistently overcome the sequential biological barriers required for therapy. Although nanocarrier engineering has enhanced siRNA stability, brain targeting, intracellular trafficking, and gene-silencing efficiency in preclinical models, manufacturing scalability, biological heterogeneity, long-term safety, reproducibility, and regulatory feasibility remain important barriers to clinical translation. Future progress will likely depend on delivery systems that integrate effective brain transport, endosomal escape, controlled intracellular release, and scalable manufacturing within clinical platforms.