RNA-based therapies for neurodegenerative disease: Targeting molecular mechanisms for disease modification

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are characterized by progressive neuronal damage, protein aggregation, and chronic inflammation, leading to cognitive and motor impairments. Despite symptomatic relief from current therapies, disease-modifying treatments targeting the core molecular mechanism are still lacking. RNA-based therapies offer a promising approach to treating neurodegenerative disease by targeting molecular mechanisms such as gene expression, protein synthesis, and neuroinflammation. Therapeutic strategies include Long non-coding RNA (lncRNA), Antisense oligonucleotides (ASOs), RNA interference (RNAi), small interfering RNA (siRNA) and short hairpin RNA (shRNA), messenger RNA (mRNA) therapies, and microRNA (miRNA)-based interventions. These therapies aim to decrease toxic protein accumulation, restore deficient proteins, and modulate inflammatory responses in conditions like AD, PD, and HD. Unlike conventional treatments that primarily manage symptoms, RNA-based therapies have the potential to modify disease progression by addressing its root causes. This review aims to provide a comprehensive overview of current RNA-based therapeutic strategies for neurodegenerative diseases, discussing their mechanism of action, preclinical and clinical advancement. It further explores innovative solutions, including nanocarrier-mediated delivery, chemical modifications to enhance RNA stability, and personalized medicine approaches guided by genetic profiling that are being developed to overcome these barriers. This review also underscores the therapeutic opportunities and current limitations of RNA-based interventions, highlighting their potential to transform the future of neurodegenerative disease management.