Multifunctional degradable highly branched–linear poly(β-amino esters) for efficient YAP gene delivery

Manipulation of the Yes-associated protein (YAP) gene offers considerable potential for elucidating cancer pathogenesis and promoting skin tissue repair. However, the development of safe and efficient YAP gene delivery systems remains a formidable challenge to accelerate its clinical application. In this study, a novel two-step linear oligomer combination branching strategy was employed to synthesize a series of highly branched-linear poly(β-amino esters) (H-LPAEs), enabling efficient transfection of the YAP gene in cancer cells. The unique branched-linear topological structure provided multiple terminal groups and a broad chemical space, allowing H-LPAEs to effectively condense DNA into nanosized polyplexes and facilitate cellular uptake. Notably, experimental studies revealed that H-LPAE-1 generally displayed exceptional gene transfection efficiency, reaching up to 76.6% across various cell types, while maintaining a superior safety profile. Furthermore, RT-PCR and western blot analyses confirmed that H-LPAE-1 mediated highly efficient YAP DNA delivery in cutaneous squamous cell carcinoma (SCC). This study not only develops an easy-to-operate "oligomer combination branching strategy" approach for synthesizing a highly branched-linear polymer, but also identifies a promising candidate for effective YAP gene delivery.