Effect of Protein Corona on Mitochondrial Targeting Ability and Cytotoxicity of Triphenylphosphonium Conjugated with Polyglycerol-Functionalized Nanodiamond
Effect of Protein Corona on Mitochondrial Targeting Ability and Cytotoxicity of Triphenylphosphonium Conjugated with Polyglycerol-Functionalized Nanodiamond
复制标题
蛋白冠对聚甘油功能化纳米金刚石缀合三苯基鏻线粒体靶向能力和细胞毒性的影响
DOI：
10.1021/acs.molpharmaceut.1c00188
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发表时间：
2021
影响因子：
4.9
通讯作者：
Komatsu Naoki
中科院分区：
文献类型：
--
作者：
Zou Yajuan;Nishikawa Masahiro;Kang Heon Gyu;Cheng Guoqing;Wang Wei;Wang Yuquan;Komatsu Naoki
靶向修饰的纳米粒子功能化在推进精密纳米医学方面具有很大的潜力。然而，已知NP表面上的靶向部分被生物流体中的蛋白质冠所掩盖，从而降低了靶向效率。虽然它已经在细胞水平上得到证实，但对蛋白质冠对亚细胞靶向的影响知之甚少。本研究采用三苯磷（triphenylphosphonium， TPP）作为线粒体靶向片段，研究了胎牛血清和人血浆蛋白冠对其靶向能力和细胞毒性的影响。具体来说，我们在聚甘油（PG）功能化的纳米金刚石（ND）表面以低(l)和高(h)密度引入TPP。尽管存在“无电晕”的PG界面，但我们发现TPP部分吸引蛋白质形成电晕层，TPP密度与蛋白质量之间存在明显的线性关系。通过对人宫颈上皮（HeLa）和人肺上皮癌（A549）细胞的研究，我们进一步证明(1)蛋白冠减轻了ND-PG-TPP-land -h的细胞毒性，(2)nd - pg - tpp -l表面少量的蛋白不影响其线粒体靶向能力。(3) nd - pg - tpp -表面大量的蛋白质通过限制内核体和溶酶体腔室内的nd而降低了其靶向特异性。我们的研究结果将为具有主动靶向部分的NPs的设计提供深入的见解，以便在亚细胞水平上更精确和更安全的递送。
Functionalization of nanoparticles (NPs) with targeting moieties has a high potential to advance precision nanomedicine. However, the targeting moieties on a NP surface are known to be masked by a protein corona in biofluids, lowering the targeting efficiency. Although it has been demonstrated at the cellular level, little is known about the influence of the protein corona on the subcellular targeting. Herein, we adopted triphenylphosphonium (TPP) as a mitochondrial targeting moiety and investigated the effects of protein coronas from fetal bovine serum and human plasma on its targeting ability and cytotoxicity. Specifically, we introduced TPP in low (l) and high (h) densities on the surface of nanodiamond (ND) functionalized with polyglycerol (PG). Despite the “corona-free” PG interface, we found that the TPP moiety attracted proteins to form a corona layer with clear linearity between the TPP density and the protein amount. By performing investigations on human cervix epithelium (HeLa) and human lung epithelial carcinoma (A549) cells, we further demonstrated that (1) the protein corona alleviated the cytotoxicity of both ND-PG-TPP-land -h, (2) a smaller amount of proteins on the surface of ND-PG-TPP-ldid not affect its mitochondrial targeting ability, and (3) a larger amount of proteins on the surface of ND-PG-TPP-hdiminished its targeting specificity by restricting the NDs inside the endosome and lysosome compartments. Our findings will provide in-depth insights into the design of NPs with active targeting moiety for more precise and safer delivery at the subcellular level.