A Two-Pronged Pulmonary Gene Delivery Strategy: A Surface-Modified Fullerene Nanoparticle and a Hypotonic Vehicle.
A Two-Pronged Pulmonary Gene Delivery Strategy: A Surface-Modified Fullerene Nanoparticle and a Hypotonic Vehicle.
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一种双叉肺基因递送策略：表面修饰的富勒烯纳米颗粒和低渗载体。
DOI：
10.1002/anie.202101732
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发表时间：
2021-07-05
期刊：
影响因子：
--
通讯作者：
Suk JS
中科院分区：
文献类型：
--
作者：
Chen D;Liu S;Chen D;Liu J;Wu J;Wang H;Su Y;Kwak G;Zuo X;Rao D;Cui H;Shu C;Suk JS
吸入基因疗法在治疗慢性肺部疾病方面具有独特的潜力，目前主要通过对症治疗进行治疗。然而，由于存在许多生物传递障碍，在肺中实现治疗相关的基因转移效果一直具有挑战性。在这里，我们介绍了一种简单的方法，克服细胞外和细胞屏障，以提高基因在体内肺中的转移效率。我们赋予四（哌嗪基）富勒烯环氧化物（TPFE）纳米颗粒非粘附表面聚乙二醇（PEG）涂层，从而使纳米颗粒能够穿过气道粘液凝胶层，避免被肺泡巨噬细胞吞噬。同时，我们利用低渗载体，通过渗透驱动的调节体积减少（RVD）机制，促进肺实质细胞对聚乙二醇化纳米颗粒的内吞吸收。我们证明，这种双管齐下的递送策略在健康小鼠和慢性肺部疾病小鼠的肺中都提供了安全、广泛传播和高水平的转基因表达，其特征是递送障碍增强。设计了表面包覆聚乙二醇（PEG）的四（哌嗪）富勒烯（TPFE）基纳米颗粒（NPs）。聚乙二醇化允许NPs避免与粘蛋白糖蛋白相互作用和巨噬细胞的吞噬摄取。NPs进入靶肺细胞后，低渗载体溶液通过渗透驱动的调节体积效应增强其内吞作用，从而提供高效的转基因表达。
Inhaled gene therapy poses a unique potential of curing chronic lung diseases, which are currently managed primarily by symptomatic treatments. However, it has been challenging to achieve therapeutically relevant gene transfer efficacy in the lung due to the presence of numerous biological delivery barriers. Here, we introduce a simple approach that overcomes both extracellular and cellular barriers to enhance gene transfer efficacy in the lung in vivo. We endowed tetra(piperazino)fullerene epoxide (TPFE)‐based nanoparticles with non‐adhesive surface polyethylene glycol (PEG) coatings, thereby enabling the nanoparticles to cross the airway mucus gel layer and avoid phagocytic uptake by alveolar macrophages. In parallel, we utilized a hypotonic vehicle to facilitate endocytic uptake of the PEGylated nanoparticles by lung parenchymal cells via the osmotically driven regulatory volume decrease (RVD) mechanism. We demonstrate that this two‐pronged delivery strategy provides safe, wide‐spread and high‐level transgene expression in the lungs of both healthy mice and mice with chronic lung diseases characterized by reinforced delivery barriers. Tetra(piperazino)fullerene (TPFE)‐based nanoparticles (NPs), surface‐coated with polyethylene glycol (PEG), were engineered. The PEGylation allows the NPs to avoid interactions with mucin glycoproteins and phagocytic uptake by macrophages. After the NPs access the target lung cells, a hypotonic vehicle solution enhances their endocytosis via the osmotically driven regulatory volume effect, thereby providing highly efficient transgene expression.
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DOI：
10.1126/science.1223012
发表时间：
2012-08-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Button B;Cai LH;Ehre C;Kesimer M;Hill DB;Sheehan JK;Boucher RC;Rubinstein M
通讯作者：
Rubinstein M
影响因子：
4.6
作者：
Minami K;Okamoto K;Doi K;Harano K;Noiri E;Nakamura E
通讯作者：
Nakamura E
DOI：
10.1016/j.jconrel.2016.05.031
发表时间：
2016-10-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Kim N;Duncan GA;Hanes J;Suk JS
通讯作者：
Suk JS
影响因子：
2
作者：
Hatakeyama, Hiroto;Akita, Hidetaka;Harashima, Hideyoshi
通讯作者：
Harashima, Hideyoshi
DOI：
10.1073/pnas.1502281112
发表时间：
2015-07-14
影响因子：
11.1
作者：
Mastorakos, Panagiotis;da Silva, Adriana L.;Suk, Jung Soo
通讯作者：
Suk, Jung Soo