Ligand Phase Separation-Promoted, "Squeezing-Out" Mode Explaining the Mechanism and Implications of Neutral Nanoparticles That Escaped from Lysosomes.
Ligand Phase Separation-Promoted, "Squeezing-Out" Mode Explaining the Mechanism and Implications of Neutral Nanoparticles That Escaped from Lysosomes.
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DOI：
10.1021/acsnano.3c09452
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发表时间：
2024-01
期刊：
影响因子：
17.1
通讯作者：
Huiyue Zhao;Yuanqiang Chen;Xing-Yu Luo;Ming Cai;Jia-Yi Li;Xin-Yu Lin;Hao Zhang;Hongming Ding-Hongmi
中科院分区：
文献类型：
--
作者：
Huiyue Zhao;Yuanqiang Chen;Xing-Yu Luo;Ming Cai;Jia-Yi Li;Xin-Yu Lin;Hao Zhang;Hongming Ding-Hongmi
用PEG或类似分子官能化的中性纳米材料已被广泛用作纳米药物。与能够利用众所周知的质子海绵效应来促进其从溶酶体中逸出的阳性对应物相比，目前尚不清楚中性物质如何进入细胞质。在这项研究中，以聚乙二醇化的中性Au纳米球为例，我们系统地研究了它们的时间依赖性转运后摄取。具体来说，我们利用耗散粒子动力学模拟来揭示纳米球如何绕过溶酶体截留，其中发现了称为“挤出”模式的机制。接下来，我们对纳米材料如何在完整性和功能性方面影响溶酶体进行了全面的研究。通过使用单分子成像，在溶酶体中用靶向部分特异性保存PEG封端支持“挤出”模式作为纳米材料的溶酶体逃逸的潜在机制。所有证据都指出，这样的过程对溶酶体是良性的，其中纳米材料的逃逸是以靶向部分损失为代价的。此外，我们证明，通过微调纳米材料从溶酶体逃逸的功效，可以很容易地实现不同途径和代谢机制的调节，从而为我们提供了一个简单而强大的工具来牵连细胞。
Neutral nanomaterials functionalized with PEG or similar molecules have been popularly employed as nanomedicines. Compared to positive counterparts that are capable of harnessing the well-known proton sponge effect to facilitate their escape from lysosomes, it is yet unclear how neutral substances got their entry into the cytosol. In this study, by taking PEGylated, neutral Au nanospheres as an example, we systematically investigated their time-dependent translocation postuptake. Specifically, we harnessed dissipative particle dynamics simulations to uncover how nanospheres bypass lysosomal entrapment, wherein a mechanism termed as "squeezing-out" mode was discovered. We next conducted a comprehensive investigation on how nanomaterials implicate lysosomes in terms of integrity and functionality. By using single-molecule imaging, specific preservation of PEG-terminated with targeting moieties in lysosomes supports the "squeezing-out" mode as the mechanism underlying the lysosomal escape of nanomaterials. All evidence points out that such a process is benign to lysosomes, wherein the escape of nanomaterials proceeds at the expense of targeting moieties loss. Furthermore, we proved that by fine-tuning of the efficacy of nanomaterials escaping from lysosomes, modulation of distinct pathways and metabolic machinery can be achieved readily, thereby offering us a simple and robust tool to implicate cells.