Combinatorial Synthesis of Alkyl Chain‐Capped Poly(β‐Amino Ester)s for Effective siRNA Delivery

Poly (β‐amino ester) (PBAE) is a class of biodegradable polymers containing ester bonds in their main chain, extensively investigated as cationic polymer carriers for siRNA. Most current PBAE carriers rely on termination with hydrophilic or charged amines. In this study, a polymer platform consisting of 168 PBAE polymers with hydrophobic alkyl chain terminals is constructed through sequential aza‐Michael addition. A large number of effective carriers are identified through in vitro screening of the PBAE platform for siLuc delivery to HeLa‐Luc cells. Specifically, PA8‐C6 and PA8‐C8 achieve remarkable gene knockdown efficacies of up to 80% with low cytotoxicity. Certain materials from the PA2 and PA5 series demonstrate potent siRNA delivery capabilities associated with elevated cytotoxicity. The pKa value of PBAE is predominantly determined by the hydrophilic amine side chains rather than the end‐capping groups. A pKa range of ≈6.2–6.5 may contribute to the excellent delivery capability for PA8 series carriers. The co‐formulation of PBAE carriers with helper lipids leads to the reduced size and surface charges of the polyplex NPs with siRNA, consequently decreasing the cytotoxicity and enhancing siRNA delivery efficacy. These findings hold significant implications for the development of novel degradable polymer carriers for siRNA delivery. Poly(β‐amino ester) (PBAE) exhibits great potential in nucleic acid delivery due to its excellent biodegradability, diverse functionality, and facile preparation. Most current PBAE carriers rely on termination with hydrophilic or charged amines. This study reports a novel polymer platform consisting of PBAEs with hydrophobic alkyl chain terminals for effective siRNA delivery