Potent gene delivery from fluorinated poly(β-amino ester) in adhesive and suspension difficult-to-transfect cells for apoptosis and ferroptosis

Tremendous efforts have been made to improve polymeric property in gene delivery performances, especially when obstacle of transferring gene construct into difficult-to-transfect cells occurs. Innovations in the area of fluorination and fluorinated compounds with biomedical potential in medicinal chemistry are believed to assist in the development of new therapeutics. Fluorine modified polymers have shown to navigate the gene transfection cellular barriers and promoted the transfection outcomes. Gene transfer into some liver cancer cells and human leukemia cells has always been a challenge. Here, by facile incorporation of a fluorine containing amine monomer, 1H,1H-undecafluorohexylamine, fluorinated poly(beta-amino ester) (FPAE) was synthesized to significantly improve the transfection performance, achieving high transfection efficiency of 87% and 55% in two representative difficult-to-transfect cells, HepG2 and Molt-4, which were cultured in adhesive and suspension condition, respectively. However, the potency of Lipofectamine 3000 was very limited. More importantly, functional studies revealed that FPAE can dramatically outperform Lipofectamine 3000 in delivering Bcl-xL and PKC beta II to either provide the protection against apoptosis or promote the ferroptosis in HepG2 cells. This work facilitates gene therapies by overcoming biological barriers for targeting difficult-to-transfect cells and disease models when medically necessary.