Albumin-binding dendrimer-conjugated siRNA enables safe and effective gene silencing throughout the central nervous system

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.