LAUSR

Ribonucleic acid (RNA) therapeutics are an emerging class of drugs. RNA aptamers are of significant therapeutic and clinical interest because their activity can be easily reversed in vivo—a useful feature that is difficult to achieve using other therapeutic modalities. Despite their therapeutic promise, RNA aptamers are limited by their poor blood circulation. The attachment of polyethylene glycol (PEG) to RNA aptamers addresses this limitation. However, an RNA aptamer‐PEG conjugate that is a reversible anticoagulant fails in a clinical trial due to the reactivity of the conjugate with pre‐existing PEG antibodies and has cast a pall over PEGylation of aptamers and other biologics, despite its long history of utility in drug delivery. Here, PEG antibody‐reactivity of this RNA aptamer is eliminated by conjugating it to a next‐generation PEG‐like brush polymer—poly[(oligoethylene glycol) methyl ether methacrylate)] (POEGMA). The conjugate retained the drug's therapeutic action and the ability to be easily reversed. Importantly, this conjugate does not bind pre‐existing PEG antibodies that are prevalent in humans and does not induce a humoral immune response against the polymer itself in mice. These findings suggest a path to rescuing the PEGylation of RNA therapeutics and vaccines from the deleterious side‐effects of PEG.