Influence of Substituent Chain Branching on the Transfection Efficacy of Cyclopropenium-Based Polymers

The realization of gene therapy relies on the development of delivery vectors with high efficiency and biocompatibility. With a multitude of structures accessible, the core challenge is precisely tuning vector structure to probe and optimize structure⁻property relationships. Employing a modular strategy, two pairs of cationic polymers based on the trisaminocyclopropenium (TAC) ion were synthesized where the substituents differ in the degree of alkyl chain branching. All TAC-based polymers exhibited higher transfection efficiencies than the untreated controls, with variable in vitro toxicities. Considering both cytotoxicity and transfection efficacy, an optimal nonviral vector was identified. Our studies highlight the importance of exercising precise control over polymer structure, both in terms of backbone identity and substituent nature, and the necessity of a robust, modular platform from which to study them.