Amphipathic dendritic poly-peptides carrier to deliver antisense oligonucleotides against multi-drug resistant bacteria in vitro and in vivo.
Amphipathic dendritic poly-peptides carrier to deliver antisense oligonucleotides against multi-drug resistant bacteria in vitro and in vivo.
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DOI：
10.1186/s12951-022-01384-y
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发表时间：
2022-04-02
影响因子：
10.2
通讯作者：
Xue X
中科院分区：
文献类型：
--
作者：
Chen Z;Hu Y;Mao X;Nie D;Zhao H;Hou Z;Li M;Meng J;Luo X;Xue X
多药耐药（MDR）细菌，尤其是革兰氏阴性细菌引起的感染爆发已成为医院和社区的全球健康问题。基于反义寡核苷酸（ASO）的治疗剂在治疗由MDR细菌引起的感染方面具有很大的前景。然而，由于其高分子量和亲水性导致的低细胞穿透效率，ASOs治疗剂被扼杀。在这里，我们设计了一系列树突状多肽，（DPP 1至DPP 12）包封ASO以形成DSPE-mPEG 2000修饰的ASO/DPP纳米颗粒（DP-AD 1至DP-AD 12），并观察到具有正电荷≥ 8的两亲性DP-AD 2、3、7或8显示出将ASO递送到细菌中的高效率，而只有DP-AD 7和DP-AD 8这两个组氨酸残基在体外对细菌生长和目的基因表达有明显的抑制作用。DP-AD 7 anti-acpP能显著提高ESBLs-E感染脓毒症小鼠的存活率。大肠杆菌，在体内表现出很强的抗菌作用。本研究首次将DPP设计成一种有效的载体，用于递送抗MDR细菌的反义寡核苷酸，并证明了DPP的两亲性、8-10个正电荷和2个组氨酸残基是有效递送所必需的，为反义抗菌策略的开发和研究提供了一种新的方法。在线版本包含补充材料，可通过10.1186/s12951-022-01384-y获得。
Outbreaks of infection due to multidrug-resistant (MDR) bacteria, especially Gram-negative bacteria, have become a global health issue in both hospitals and communities. Antisense oligonucleotides (ASOs) based therapeutics hold a great promise for treating infections caused by MDR bacteria. However, ASOs therapeutics are strangled because of its low cell penetration efficiency caused by the high molecular weight and hydrophilicity. Here, we designed a series of dendritic poly-peptides (DPP1 to DPP12) to encapsulate ASOs to form DSPE-mPEG2000 decorated ASOs/DPP nanoparticles (DP-AD1 to DP-AD12) and observed that amphipathic DP-AD2, 3, 7 or 8 with a positive charge ≥ 8 showed great efficiency to deliver ASOs into bacteria, but only the two histidine residues contained DP-AD7 and DP-AD8 significantly inhibited the bacterial growth and the targeted gene expression of tested bacteria in vitro. DP-AD7anti-acpP remarkably increased the survival rate of septic mice infected by ESBLs-E. coli, exhibiting strong antibacterial effects in vivo. For the first time, we designed DPP as a potent carrier to deliver ASOs for combating MDR bacteria and demonstrated the essential features, namely, amphipathicity, 8–10 positive charges, and 2 histidine residues, that are required for efficient DPP based delivery, and provide a novel approach for the development and research of the antisense antibacterial strategy. The online version contains supplementary material available at 10.1186/s12951-022-01384-y.
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影响因子：
12.4
作者：
Crombez, Laurence;Aldrian-Herrada, Gudrun;Divita, Gilles
通讯作者：
Divita, Gilles
鲍曼不动杆菌中两亲性细胞穿透肽有效递送反义寡核苷酸
影响因子：
2.4
作者：
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通讯作者：
Xue, Xiaoyan
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影响因子：
14
作者：
Bai, Hui;You, Yu;Luo, Xiaoxing
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影响因子：
3.7
作者：
Bai H;Sang G;You Y;Xue X;Zhou Y;Hou Z;Meng J;Luo X
通讯作者：
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影响因子：
17.1
作者：
Hou, Kirk K.;Pan, Hua;Ratner, Lee;Schlesinger, Paul H.;Wickline, Samuel A.
通讯作者：
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