Effective and Selective Anti-Cancer Protein Delivery via All-Functions-in-One Nanocarriers Coupled with Visible Light-Responsive, Reversible Protein Engineering
Effective and Selective Anti-Cancer Protein Delivery via All-Functions-in-One Nanocarriers Coupled with Visible Light-Responsive, Reversible Protein Engineering
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通过全功能合一纳米载体与可见光响应、可逆蛋白质工程相结合，有效、选择性地输送抗癌蛋白质
DOI：
10.1002/adfm.201706710
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发表时间：
2018-04-05
影响因子：
19
通讯作者：
Yin, Lichen
中科院分区：
文献类型：
--
作者：
He, Hua;Chen, Yongbing;Yin, Lichen
有效的蛋白药物细胞内递送和肿瘤特异性蛋白功能的激活是抗癌蛋白治疗的关键。然而，目前还缺乏一种既能协调复杂的系统屏障，又能在时空上操纵蛋白质功能的全能蛋白质传递系统。本文开发了一种“多功能一体”的掺杂光敏剂（PS）的纳米载体，并结合活性氧（ROS）响应的可逆蛋白质工程，利用低功率密度（5 mW cm(-2)）的长波可见光（635 nm）实现了靶向癌症的蛋白质递送和蛋白质活性的时空操纵。特别是，RNase A被h2o2可切割的苯硼酸笼化，形成4-硝基苯基4-（4,4,5,5-四甲基-1,3,2-二恶硼酸-2-基）碳酸苄酯（NBC）修饰的RNase (RNBC), RNase （RNBC）被包裹在酸降解的、金属交联的PEI （KPEI）基纳米配合物（nc）中，纳米配合物被ps修饰的透明质酸（HA）包裹。这些NCs协调了蛋白质递送的关键过程，其中HA涂层使NCs具有长血液循环和癌细胞靶向性，KPEI使内体逃逸以及酸触发的细胞内RNBC释放。肿瘤特异性光照射产生H2O2，杀死癌细胞，恢复蛋白质活性，达到协同抗癌效果。这是第一次通过将ROS可切割的蛋白质笼化与ps介导的ROS生成相结合来对蛋白质功能进行光电操纵，这种“多功能一体”的纳米载体代表了程序化抗癌蛋白递送的一个有希望的例子。
Efficient intracellular delivery of protein drugs and tumor-specific activation of protein functions are critical toward anti-cancer protein therapy. However, an omnipotent protein delivery system that can harmonize the complicated systemic barriers as well as spatiotemporally manipulate protein function is lacking. Herein, an "all-functions-in-one" nanocarrier doped with photosensitizer (PS) is developed and coupled with reactive oxygen species (ROS)-responsive, reversible protein engineering to realize cancer-targeted protein delivery, and spatiotemporal manipulation of protein activities using long-wavelength visible light (635 nm) at low power density (5 mW cm(-2)). Particularly, RNase A is caged with H2O2-cleavable phenylboronic acid to form 4-nitrophenyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl carbonate (NBC)-modified RNase (RNBC), which is encapsulated in aciddegradable, ketal-crosslinked PEI (KPEI)-based nanocomplexes (NCs) coated with PS-modified hyaluronic acid (HA). Such NCs harmonize the critical processes for protein delivery, wherein HA coating renders NCs with long blood circulation and cancer cell targeting, and KPEI enables endosomal escape as well as acid-triggered intracellular RNBC release. Tumor-specific light irradiation generates H2O2 to kill cancer cells and restore the protein activity, thus achieving synergistic anti-cancer efficacy. It is the first time to photomanipulate protein functions by coupling ROS-cleavable protein caging with PS-mediated ROS generation, and the "all-functions-in-one" nanocarrier represents a promising example for the programmed anti-cancer protein delivery.