Engineering therapeutic delivery vehicles via exploration of novel polycation moieties and topologies hinges on the development of facile synthesis and assembly methods. The design space is vast when considering polycation chemistry and architecture along with the many nucleic acid types; indeed, numerous factors collectively influence biological performance. Linear cationic polymers can readily bind nucleic acids to form nanocomplexes termed polyplexes. When polycations are chain extended with hydrophobic monomers, amphiphilic block polymers result that can form micelles in aqueous solution. These self-assembled nanostructures can bind nucleic acids via the cationic micelle corona and offer precision in structure and enhanced performance compared to polyplexes. Further, bottlebrush polymers combine principles of both polyplexes and micelleplexes into unimolecular nanostructures, where polycationic macromonomers are covalently pinned together via ring opening polymerization. We report the synthesis and assembly of several homopolycations differing in cation identity along with analogous amphiphilic diblock variants, poly(n-butyl acrylate)-b-poly(cationic acrylamide), which contain the same cationic groups in their hydrophilic corona. The polycations were obtained through the parallel post-polymerization modification of a poly(n-butyl acrylate)-b-poly(pentafluorophenyl acrylate) reactive scaffold, which granted polymers with equivalent degrees of polymerization and subsequent quantitative functionalization with cations of different pKa. Further, cationic unimolecular bottlebrush polymers have also been synthesized via ring opening metathesis polymerization. The complexation of these various architectures with antisense oligonucleotides, plasmids, and gene editing payloads have been extensively explored for binding, stability, delivery and toxicity of polynucleotide payloads. General trends have been discerned and will be discussed relating vehicle chemistry and architecture to biological performance.

Polycation architecture affects complexation and delivery of nucleic acid drugs: Comparing polymer, micelle, and bottlebrush vehicles

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