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

Improving siRNA delivery to the central nervous system (CNS) is a major focus for treating the numerous debilitating neurological conditions which 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 six 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.