Nonhepatic delivery of small interfering RNAs (siRNAs) remains a challenge for development of RNA interference-based therapeutics. We report a noncationic vector wherein linear poly(ethylene glycol) (PEG), a polymer generally considered as inert and safe biologically but ineffective as a vector, is transformed into a bottlebrush architecture. This topology provides covalently embedded siRNA with augmented nuclease stability and cellular uptake. Consisting almost entirely of PEG and siRNA, the conjugates exhibit a ~25-fold increase in blood elimination half-life and a ~19-fold increase in the area under the curve compared with unmodified siRNA. The improved pharmacokinetics results in greater tumor uptake and diminished liver capture. Despite the structural simplicity these conjugates efficiently knock down target genes in vivo without apparent toxic and immunogenic reactions. Given the benign biological nature of PEG and its widespread precedence in biopharmaceuticals, we anticipate the brush polymer-based technology to have a significant impact on siRNA therapeutics.