Albumin-binding dendrimer-conjugated siRNA enables safe and effective gene silencing throughout the central nervous system
Year: 2026
Type: article
Abstract: Improving siRNA delivery to the central nervous system (CNS) is a major focus for treating the numerous debilitating neurological conditions that have a genetic basis. Here, we present an albumin-binding siRNA based on an amphiphilic dendrimer conjugate (D-siRNA). We demonstrate that D-siRNA achieves effective and homogeneous delivery throughout the CNS following administration into the cerebrospinal fluid (CSF). In mice, a single CSF administration of D-siRNA resulted in potent and durable gene silencing across various brain regions, with effects lasting 6 months without detectable toxicity. We validate its utility in larger rodents (rats) using intrathecal administration-a clinically relevant route-showing effective and broad delivery and robust silencing. Benchmarking against other clinically relevant siRNA delivery scaffolds revealed that D-siRNA provides comparable delivery and efficacy, with more efficient conversion of gross uptake to functional uptake. These findings support the use of albumin-binding conjugates for brain delivery, and position D-siRNA as a safe, effective, and durable platform for gene silencing in the CNS.
Source: Nucleic Acids Research
DOI: 10.1093/nar/gkag926
Authors: Hassan H Fakih, Masahiro Ohara, Ashley Summers, Samantha L Sarli, Karen Kelly, Rosemary Gagnon, Bruktawit Maru, Brianna Bramato, Anastasia Khvorova, Jonathan K Watts
Institution: University of Massachusetts Chan Medical School
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,992
Awards: Mid-Scale RNA Synthesis, Purification and Quality Control System, High-throughput Oligonucleotide Production System, G9000017674, Expanding the Chemical Diversity of Therapeutic Oligonucleotides, Multi-Targeting Oligonucleotide Therapeutics for Familial and Sporadic Amyotrophic Lateral Sclerosis
OpenAlex ID: W7116054809