Precise PBAEs: A Highly Efficient Single-Molecularly Defined Gene-Delivery System

Gene-delivery polymers have wide therapeutic applications. The structures (e.g., molecular weight, polymer sequence, end groups, and topology) of gene-delivery polymers are of crucial importance to their properties including transfection efficiency, toxicity, and targeting capability. Thus, precise control over the structures of gene-delivery polymers is extremely beneficial for property optimizations and manufacturing reproducibility. However, sequence-defined gene-delivery polymers with high efficiency and low toxicity are rare, limited by synthetic strategies. In this work, we developed a method that enables poly(beta-amino esters), one of the most promising gene-delivery polymers, to be synthesized with precisely controlled and vastly variable molecular weight, end group, and topology. The precise PBAEs exhibited advantages over the corresponding random PBAEs (i.e., the same high level of transfection efficiency at a much lower molecular weight), and their defined structures unambiguously revealed new design principles for gene-delivery polymers.