Elucidating the Relationship Between Physicochemical Properties and Gene Delivery of Covalently Tethered Cationic Surfactants

Synthetic cationic lipids are the most widely used non‐viral nucleic acid delivery vectors. However, the efficiency of cationic lipids is currently inferior to that of viral vectors, necessitating the development of novel molecules. Gemini surfactants outperform corresponding conventional monomeric surfactants in characteristics such as high surface activity, extraordinarily low critical aggregate concentration (CAC), unusual rheological properties, and better wetting ability due to their unique self‐assembly properties. Structure–activity relationship studies on higher generation surfactants with two or more hydrocarbon chains in the context of gene delivery are not reported. In the current study, we evaluated the physicochemical and gene transfection properties of surfactants consisting two and three quaternary ammonium charges on the head group covalently connected by an ethylene linker. Fundamental physicochemical analyses, including CAC, dynamic light scattering, transmission electron microscopy, and DNA‐binding studies, were performed, ensuring their suitability as nucleic acid delivery agents for cell lines, in vitro. Our findings revealed distinct surface properties of self‐assembled particles from three surfactants studied, strongly associated with their DNA condensation and subsequent intracellular delivery. The current study shed light on the relationship between self‐assembly properties and gene delivery efficacy of extended surfactants with covalently tethered cationic headgroups in comparison with conventional single‐tailed surfactants.