Neurodegenerative diseases (NDDs) encompass a spectrum of age-associated conditions marked by progressive deterioration and loss of neuronal populations (Gadhave et al., 2024). As global life expectancy increases, these disorders are becoming increasingly prevalent, representing a significant public health concern worldwide (Lamptey et al., 2022). The global incidence of NDDs is estimated to be approximately 10 to 15 cases per 100,000 individuals annually (Scarian et al., 2024; Onohuean et al., 2022). A hallmark of many NDDs is the accumulation of misfolded proteins either within the neurons or in the extracellular space (Soto and Pritzkow, 2018). For instance, PD is characterized by intracellular aggregates of alpha-synuclein, while AD involves extracellular amyloid beta plaque and intracellular tau tangles (Calabresi et al., 2023; Ayaz et al., 2024). HD is associated with mutant huntingtin protein containing expanded polyglutamine repeats (Juenemann et al., 2013). Current therapeutic approaches primarily aim to alleviate symptoms without modifying disease progression (Oyovwi et al., 2025). AD therapies like acetylcholinesterase inhibitors (donepezil, rivastigmine) and NMDA receptor antagonists (memantine) help alleviate symptoms but do not stop or reverse neuronal damage (Marucci et al., 2021). Similarly, in Parkinson's disease, levodopa and dopamine agonists temporarily improve motor symptoms but fail to prevent the progressive loss of dopaminergic neurons (Ramesh and Arachchige, 2023; Charvin et al., 2018). In HD, vesicular monoamine transporter 2 (VMAT2) such as tetrabenazine are employed to manage chorea by depleting presynaptic dopamine (Nikkhah, 2021). These treatments do not address the underlying pathogenic mechanism, highlighting the need for disease modifying therapies.

In this context, RNA-based therapies have emerged as a promising new class of treatments with the potential to address many of these challenges (Zhu et al., 2022). These therapies function by modulating gene expression at the RNA level, allowing for precise regulation of pathogenic or deficient genes (Zhu et al., 2022). Various types of RNA-based modalities have been developed, including lncRNA, ASOs, which bind to mRNA to modify splicing or promote degradation; small siRNAs, which silence genes through RNA interference (Bajan and Hutvagner, 2020); microRNAs (miRNAs), which regulate gene networks and can be therapeutically targeted (Diener et al., 2022); mRNA therapies, which introduce functional proteins in cases of genetic deficiency and RNA aptamers, which bind specific targets to exert therapeutic effects or assist in drug delivery (Guan and Zhang, 2020). Unlike traditional drugs, RNA therapeutics can be designed to engage previously inaccessible targets, offering a highly adaptable and targeted approach to treating neurodegenerative diseases. Additionally, these therapies can modulate neuroinflammation and cellular pathways involved in disease progression (Marino et al., 2022). Certain miRNAs have been identified as key regulators of neuroinflammatory responses, and the therapeutic modulation of these small RNA molecules could help suppress excessive inflammation and protect neurons (Zhang et al., 2023). RNA aptamers, another class of RNA therapeutics, function like antibodies by binding to specific target molecules, potentially neutralizing toxic protein aggregates such as amyloid-beta in AD or alpha-synuclein in PD (Wang et al., 2024).

Another notable advantage of RNA therapeutics is their potential for personalized medicine. Because these therapies can be designed to specifically target individual genetic mutations, they hold promise for treating patients with rare genetic forms of neurodegenerative diseases (Tambuyzer et al., 2020). Advances in sequencing technologies and bioinformatics enable the development of customized RNA-based interventions tailored to an individual's genetic profile, enhancing the effectiveness of treatment and minimizing adverse effects (Zalli et al., 2023). Despite their potential, RNA-based therapies face significant challenges. These include poor intracellular delivery due to their large size and negative charge, instability from degradation by nucleases, and the difficulty of crossing the blood–brain barrier (BBB) (Ali Zaidi et al., 2023; Qu et al., 2024; Shi et al., 2024a, Shi et al., 2024b). However, effective delivery to the central nervous system remains a major obstacle due to the highly selective nature of the BBB, which restricts the passage of most therapeutic agents. Nanocarrier-based strategies show promise in enhancing RNA delivery across the BBB. These include the use of permeation enhancers, P-glycoprotein inhibitors to reduce efflux, and surface modifications with ligands targeting brain-specific receptors (Hersh et al., 2016). Furthermore, to overcome these hurdles, protective delivery systems such as lipid nanoparticles, viral vectors, and chemical modifications have been developed to improve bioavailability and stability (Hou et al., 2021; Yan et al., 2022). Due to the limitations of existing therapies, there is an urgent need to explore innovative approaches that target the root causes of NDDs. RNA-based therapies have emerged as a promising strategy, offering the potential to modulate gene expression and address the molecular mechanisms underlying these diseases. Therefore, this review aims to provide a comprehensive and critical overview of emerging RNA-based therapeutic strategies for neurodegenerative diseases (NDDs), with a particular focus on the mechanisms, therapeutic targets, delivery challenges, and clinical potential of various RNA modalities, including lncRNA, ASO, siRNAs, miRNAs, mRNA therapies, and RNA aptamers. By highlighting recent advancements and addressing current limitations, this review seeks to underscore the transformative potential of RNA therapeutics in modifying neurodegenerative disease progression.