题目：

Engineering the Aromaticity of Cationic Helical Polypeptides toward  “Self-Activated” DNA/siRNA Delivery

作者：

Fangfang Li,^a,1 Yongjuan Li, ^a,1 Zhuchao Zhou,^b,1 Shixian Lv, ^aQiurong Deng,^a XinXu,^a Lichen Yin^a,*

单位：

^aJiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Institute of Functional Nano and Soft Materials (FUNSOM), Soochow University, Suzhou 215123, China.

^bDepartment of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China.

摘要：

The development of potent yet non-toxic membrane penetrating materials is highly demanded toward effective intracellular gene delivery. We have recently developed α-helical polypeptides which afford potent membrane activities to facilitate intracellular DNA delivery via both endocytosis and the non-endocytic “pore formation” mechanism. Endocytosis will cause endosomal entrapment of the DNA cargo, while excessive “pore formation” would cause appreciable cytotoxicity. Additionally, helical polypeptides with stiff, rod-like structure suffer from low siRNA binding affinity. To address such critical issues, we herein incorporated various aromatic domains (benzyl, naphthyl, biphenyl, anthryl, and pyrenyl) into the side-chain terminals of guanidine-rich, helical polypeptides, wherein the flat-rigid shape, π-electronic structures of aromatic motifs “self-activated” the membrane penetrating capabilities of polypeptides to promote intracellular gene delivery. Benzyl (Bn)- and naphthyl (Naph)-modified polypeptides demonstrated the highest DNA uptake level that outperformed the un-modified polypeptide, P2, by ~4 fold. More importantly, compared with P2, Bn- and Naph-modified polypeptides allowed more DNA cargoes to be internalized via the non-endocytic pathway, which greatly bypassed the endosomal entrapment and accordingly enhanced the transfection efficiency by up to 42 fold, outperforming PEI 25k as the commercial reagent by 3-4 orders of magnitude. The aromatic modification also improved the siRNA condensation capability of polypeptides, achieving notably enhanced gene silencing efficiency against tumor necrosis factor-α (TNF-α) to treat acute hepatic inflammation. Furthermore, we unraveled that aromaticity-augmented membrane activity was accompanied with comparable or even significantly reduced “pore formation” capability, thus leading to diminished cytotoxicity at high concentrations. This study therefore provides a promising approach to manipulate the membrane activities and penetration mechanisms of polycations, which overcomes the multiple critical barriers against effective and safe gene delivery.

影响因子：

7.5

分区情况：

一区

链接：

http://pubs.acs.org/doi/10.1021/acsami.7b08534