Multifunctional Poly(amine-co-ester-co-orthoester) for Efficient and Safe Gene Delivery

Cationic polymers are used for nonviral gene delivery, but current materials lack the functionality to address the multiple barriers involved in gene delivery. Here we describe the rational design and synthesis of a new family of quaterpolymers with unprecedented multifunctionality: acid sensitivity, low cationic charge, high hydrophobicity, and biodegradability, all of which are essential for efficient and safe gene delivery. The polymers were synthesized via lipase-catalyzed polymerization of orthoester diester, lactone, dialkyl diester, and amino diol monomers. Polymers containing orthoester groups exhibited acid-sensitive degradation at endosomal pH (4–5), facilitated efficient endosomal escape and unpackaging of the genes, and were efficient in delivering genetic materials to HEK293 cells, human glioma cells, primary mouse melanoma cells, and human umbilical vein endothelial cells (HUVECs). We also developed a highly efficient lyophilized formulation of the nanoparticles, which could be stored for a ...