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

Abstract 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( β ‐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. This synthetic strategy creates a new family of gene‐delivery polymers with defined structures, offering significant potentials and revealing new design principles.