Why siRNA Delivery Keeps Failing in Neurodegenerative Diseases

For more than two decades, small interfering RNA has promised something that conventional drugs for neurodegenerative disease cannot: the ability to reach into a neuron and switch off the specific gene driving pathology. Yet while RNAi therapeutics have already reached the clinic for liver disorders, patients with Alzheimer’s, Parkinson’s and Huntington’s disease still have no disease-modifying siRNA option. A review published in Molecular Biology Reports by Gülfem Erbil, Damla Aykora and Metehan Uzun of Çanakkale Onsekiz Mart University argues that the failure is not a failure of the silencing mechanism itself. It is a failure of delivery, and it is a failure that compounds at every biological barrier the therapeutic RNA encounters on its way to the cytosol.

The review adopts what the authors call a barrier-oriented framework, following a single siRNA molecule through the sequential challenges of systemic administration. The first obstacles are extracellular. Naked siRNA is a fragile double-stranded molecule roughly 21 to 23 nucleotides long, and it is rapidly degraded by ribonucleases in blood. Chemical modification of the sugar-phosphate backbone can confer nuclease resistance, but the literature shows how narrow the margin is: studies cited in the review demonstrate that a single modification at position 14 of the guide strand, or the removal of the phosphodiester backbone in the guide’s 3′ terminal region, can abolish RISC loading and target cleavage. Stability engineering must therefore preserve the precise structural features that the RNA interference machinery recognizes, a constraint that has shaped every siRNA drug design since the first stabilized candidates entered animal models in 2005.

Even a chemically stabilized siRNA faces unfavorable pharmacokinetics. Systemically delivered RNA is cleared by the kidney and liver within minutes to hours, and it is sequestered by immune recognition pathways. The review emphasizes that double-stranded RNA is inherently immunostimulatory: Toll-like receptors and cytosolic RNA sensors can trigger interferon responses, and off-target transcript silencing through partial sequence complementarity remains a persistent safety concern. Position-specific chemical modifications can reduce off-target effects, but each design choice trades silencing potency against immune evasion, and the review notes that the elimination pathways of systemically delivered siRNA are still only partially mapped.

The most formidable extracellular barrier is the blood-brain barrier. This interface of specialized endothelial cells joined by tight junctions, basement membrane, and astrocytic endfeet excludes molecules larger than roughly 400 daltons and permits less than 2 percent of candidate central nervous system drugs to cross. Efflux transporters of the ABC family actively pump lipophilic compounds back into blood, and the glycocalyx on the luminal surface presents a further electrostatic hurdle. For siRNA, which carries a polyanionic backbone and a molecular weight near 13 kilodaltons, passive diffusion across this barrier is essentially zero. The review synthesizes evidence from nanomaterial studies showing that only engineered carriers, whether lipid nanoparticles, polymeric complexes or exosomes, achieve measurable brain transport, and even then the fraction of the injected dose reaching parenchymal neurons remains vanishingly small.

Once across the barrier, the carrier must find the right cell. The review distinguishes shared limitations from disease-specific challenges by examining evidence from Alzheimer’s, Parkinson’s and Huntington’s disease. In Alzheimer’s disease, targets include BACE1 and amyloid precursor protein, and neuron-targeted nanocomplexes have shown preclinical reductions in amyloid pathology. In Parkinson’s disease, the neuroinflammatory microenvironment dominated by activated microglia and astrocytes creates both an opportunity and a complication: ligand-functionalized lipid nanoparticles can redirect siRNA to microglia through mannose receptors or to astrocytes through adenosine conjugation, but the heterogeneity of glial states means that a carrier tuned for one disease stage may fail in another. In Huntington’s disease, antisense oligonucleotide trials targeting huntingtin expression have reached patients, providing a translational benchmark that siRNA platforms have yet to match.

The review evaluates four major nanocarrier platforms against these barriers. Lipid-based nanoparticles, the platform behind the approved RNAi drug patisiran, benefit from six decades of engineering and can incorporate ionizable lipids whose protonation in the acidic endosome drives membrane disruption. Polymeric nanocarriers, particularly poly(beta-amino ester)s, offer tunable biodegradability and bioreducible linkages that release cargo in the reducing cytosol. Engineered exosomes, the natural vesicles that cells use for intercellular communication, cross the blood-brain barrier with remarkable efficiency when surface-modified with targeting peptides such as rabies virus glycoprotein, and have shown preclinical delivery of siRNA against RIPK3 that slowed neurodegenerative progression in Alzheimer’s models. Hybrid platforms combine lipid and polymer components to balance stability, endosomal escape and controlled release, but the review notes that each additional engineering layer complicates manufacturing and regulatory characterization.

Perhaps the most stubborn intracellular barrier is endosomal entrapment. Quantitative imaging studies cited in the review show that only a small fraction of internalized siRNA escapes the endolysosomal pathway, and single-cell dose-response measurements reveal that cytosolic delivery follows a steep threshold: below a critical intracellular concentration, no gene silencing occurs regardless of how much RNA the cell has taken up. Strategies to improve escape include pH-responsive ionizable lipids, charge-invertible peptides that release siRNA in response to cytoplasmic pH, and engineered lipid phases that promote inverted hexagonal structures during endosomal acidification. Yet the review concludes that no platform has consistently achieved the combination of efficient brain transport, endosomal escape and controlled intracellular release within a single clinically scalable system.

The translational record reflects these constraints. The review highlights mivelsiran (ALN-APP), the first investigational RNAi therapeutic targeting amyloid precursor protein for Alzheimer’s disease, which has completed single and multiple ascending dose Phase 1 studies. It also notes QPI-1007, an siRNA candidate that reached Phase 2/3 for ischemic optic neuropathy, demonstrating that siRNA can reach clinical endpoints in neurological contexts when delivery is feasible. But the review is candid that preclinical mouse models rarely mimic the transcriptome of human neurodegenerative disease, and that biological heterogeneity, long-term safety, reproducibility and regulatory feasibility remain barriers that nanocarrier engineering has not resolved. Manufacturing scalability is a particular concern: microfluidic synthesis of lipid nanoparticles improves reproducibility but has not yet been validated at industrial scale for brain-targeted formulations.

The review’s conclusion is measured but pointed. Nanocarrier engineering has enhanced siRNA stability, brain targeting, intracellular trafficking and gene-silencing efficiency in preclinical models, and the field has moved from cataloguing delivery systems to understanding which barriers each platform addresses. Future progress, the authors argue, will depend on delivery systems that integrate effective brain transport, endosomal escape, controlled intracellular release and scalable manufacturing within clinical platforms, rather than optimizing any single barrier in isolation. For a field that has watched RNAi transform liver therapy while central nervous system targets remained out of reach, the message is that the silencing machinery works. What remains is the delivery problem, and it is a problem that must be solved sequentially, not piecemeal.

Subject of Research: Neuroscience

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

Article References: Erbil, G., Aykora, D., & Uzun, M. (2026). Why does siRNA delivery still fail in neurodegenerative diseases? Biological barriers, nanocarrier engineering, and future translational directions. Molecular Biology Reports, 53(1), Article 1742. https://doi.org/10.1007/s11033-026-12937-x

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12937-x

Keywords: siRNA, neurodegenerative diseases, nanocarriers, blood-brain barrier, gene silencing, drug delivery, does, delivery, still, fail, neurodegenerative, diseases