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Dendrimer, such as dendrigraft poly-L-lysine (DGL) polymers, with high surface charge density, well-defined structure, and narrow poly-dispersity is often employed as a gene vector, but its transfection efficiency is still partially inhibited due to poor endosomal escape ability. Herein, we used a surface modification strategy to enhance the endosomal escape ability of DGL polymers, and thus improved its gene transfection efficiency. A library of phenylboronic acid (PBA) modified DGL polymers (PBA-DGLs) was designed to screen efficient small interfering RNA (siRNA) vectors. The lead candidate screened from the library shown a capability of inducing nearly 90% gene silencing in MDA-MB-231 cells. The study of the transfection mechanism revealed that PBA modification not only improves siRNA cellular uptake, but, more importantly, endows DGL polymers the ability of endosomal escape. One of the top candidates from polyplexes was further shielded with hyaluronic acid to construct targeted nanoparticles, and the yielding nanoparticles significantly suppressed the tumor growth in a breast cancer model by effective siRNA delivery. This research provides a general and effective strategy to enhance the endosomal escape and transfection efficiency of dendrimer.
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