Enabling safer, more potent oligonucleotide therapeutics with bottlebrush polymer conjugates

Oligonucleotide therapeutics have the unique ability to address traditionally undruggable targets through various target engagement pathways. However, despite advances in chemically modified oligonucleotides and carrier-assisted delivery systems such as lipid nanoparticles and protein/peptide conjugates, the development of oligonucleotide drugs is still plagued with lackluster potency, narrow therapeutic window, poor delivery to non-liver target sites, and/or high potential for toxicity and unwanted immune system activation. In this perspective, we discuss an unconventional delivery solution based upon bottlebrush polymers, which overcomes many key challenges in oligonucleotide drug development. We address the molecular basis of the polymer's ability to enhance tissue bioavailability and drug potency, reduce side effects, and suppress anti-carrier immunity. Furthermore, we discuss the potential of the technology in advancing oligonucleotide-based therapies for non-liver targets.