Multifunctional Degradable Highly Branched-linear Poly (β-amino esters) for Efficient YAP Gene Delivery

Abstract

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), and 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 the H-LPAE-1 generally displayed exceptional gene transfection efficiency, reaching up to 76.6% across various cell types, while maintaining superior the 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 developed an easy-to-operate “Oligomer Combination Branching Strategy” approach for synthesizing highly branched-linear polymer, but also identifies a promising candidate for effective YAP gene delivery.