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Zwitterionic Polymer Lipid Nanoparticles Enabling Selective Organ Targeting Delivery of Small Interfering RNA for the Treatment of Hepatic and Pulmonary?…

Published:4 December 2024 DOI: 10.1002/smll.202407040
Jiaxin Li, Nan Wang, Wen Zhang, Chen Peng, Xinyue Zhang, Muzi Li, Guanghui Ouyang, Yan Li

Abstract

Lipid nanoparticles (LNPs) are clinically advanced small interfering RNA (siRNA) carriers, which can prevent the breakdown of siRNA during delivery and deliver siRNA into the cytoplasm to down-regulate the target gene. However, clinical LNPs are limited to the liver, and enhancing extrahepatic targeting is vital to expand the application of LNPs in vivo. Here, zwitterionic polymer LNPs (ZP-LNPs) are assembled with the zwitterionic polymer polycarboxybetaine (PCB) modified 1,2-dimyristoylglycerol (DMG) lipid DMG-PCBn can selectively deliver siRNA to liver and lung, respectively. Three libraries with 90 ZP-LNPs are established by adjusting the degree of polymerization of DMG-PCBn, the molar ratio of lipids, and the mass ratio between lipids and siRNA. Physicochemical and in vivo biodistribution results show that B4-3@siRNA and B5-1@siRNA with high siRNA encapsulation efficiency (>85%) achieve targeted siRNA delivery to the liver and lung, respectively. The mechanism findings indicate that pKa and protein corona are essential to determine the in vivo fate of ZP-LNPs and tendency for specific organs. Importantly, these two ZP-LNPs with siTNF-α can effectively reduce the levels of tumor necrosis factor α (TNF-α) in mice with hepatic inflammation and pulmonary inflammation, respectively, indicating their promising application for the treatment of diseases associated with liver and lung.

Substances (5)

Materials
Procduct Name CAS Molecular Formula Supplier Price
1,2-Distearoyl-sn-glycero-3-phosphocholine 816-94-4 C44H88NO8P 345 suppliers $7.00-$5400.00
2-Oxetanone 57-57-8 C3H4O2 216 suppliers $22.23-$1755.00
DLin-MC3-DMA 1224606-06-7 C43H79NO2 194 suppliers Inquiry
FETUIN 9014-81-7 NULL 92 suppliers $37.07-$4810.00
DAPI 47165-04-8 C16H15N5 16 suppliers $504.53-$1715.00

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