Department of Pharmaceutics, School of Pharmacy , Fudan University and Key Laboratory of Smart Drug Delivery, Ministry of Education , Shanghai 201203 , China.
Innovation Research Institute of Traditional Chinese Medicine , Shanghai University of Traditional Chinese Medicine , Shanghai 201203 , China.
ACS Nano. 2019 Apr 23;13(4):4148-4159. doi: 10.1021/acsnano.8b08964. Epub 2019 Mar 19.
Pore-forming toxins (PFTs) are the most common bacterial virulence proteins and play a significant role in the pathogenesis of bacterial infections; thus, PFTs are an attractive therapeutic target in bacterial infections. Inspired by the pore-forming process and mechanism of PFTs, we designed an integrated hybrid nanovesicle-the erythroliposome (called the RM-PL)-for PFT detoxification by fusing natural red blood cell (RBC) membranes with artificial lipid membranes. The lipid and RBC membranes were mutually beneficial when integrated into a hybrid nanovesicle structure. The RBC membrane endowed RM-PLs with the capacity for detoxification, while the PEGylated lipid membrane stabilized the RM-PLs and greatly improved the detoxification capacity of the RBC membrane. With α-hemolysin (Hlα) as a model PFT, we demonstrated that RM-PLs could not only significantly reduce the toxicity of Hlα to erythrocytes in vitro but also effectively sponge Hlα in vivo and rescue mice from Hlα-induced damage. Moreover, the high detoxification capacity of RM-PLs was shown to be partly related to the expression of the Hlα receptor protein, a disintegrin and metalloproteinase domain-containing protein 10 on the RBC membrane. Consequently, as a component integrating natural and artificial materials, the erythroliposome nanoplatform inspires potential strategies for antivirulence therapy.
孔形成毒素 (PFTs) 是最常见的细菌毒力蛋白,在细菌感染的发病机制中起着重要作用;因此,PFTs 是细菌感染治疗的一个有吸引力的靶点。受 PFT 孔形成过程和机制的启发,我们设计了一种整合的混合纳米囊泡——赤藻糖脂体 (称为 RM-PL),通过将天然红细胞 (RBC) 膜与人工脂质膜融合来实现 PFT 解毒。当脂质和 RBC 膜整合到混合纳米囊泡结构中时,它们是相互有益的。RBC 膜赋予 RM-PLs 解毒能力,而 PEG 化脂质膜稳定了 RM-PLs,并大大提高了 RBC 膜的解毒能力。以α-溶血素 (Hlα) 为模型 PFT,我们证明 RM-PLs 不仅可以显著降低 Hlα 对体外红细胞的毒性,还可以有效地在体内吸收 Hlα 并挽救 Hlα 诱导的损伤小鼠。此外,RM-PLs 的高解毒能力部分与 RBC 膜上 Hlα 受体蛋白、一种解整合素和金属蛋白酶域蛋白 10 的表达有关。因此,作为整合天然和人工材料的组成部分,赤藻糖脂体纳米平台为抗毒力治疗提供了潜在的策略。