Complexation Preferences of Dynamic Constitutional Frameworks as Adaptive Gene Vectors

The growing applications of therapeutic nucleic acids requires the concomitant development of vectors that are optimized to complex one type of nucleic acid, forming nanoparticles suitable for further trafficking and delivery. While fine‐tuning a vector by molecular engineering to obtain a particular nanoscale organization at the nanoparticle level can be a challenging endeavor, we turned the situation around and instead screened the complexation preferences of dynamic constitutional frameworks toward different types of DNAs. Dynamic constitutional frameworks (DCF) are recently‐identified vectors by our group that can be prepared in a versatile manner through dynamic covalent chemistry. Herein, we designed and synthesized 40 new DCFs that vary in hydrophilic/hydrophobic balance, number of cationic headgroups. The results of DNA complexation obtained through gel electrophoresis and fluorescent displacement assays reveal binding preferences of different DCFs toward different DNAs. The formation of compact spherical architectures with an optimal diameter of 100–200 nm suggests that condensation into nanoparticles is more effective for longer PEG chains and PEI groups that induce a better binding performance in the presence of DNA targets.