Journal
NANO LETTERS
Volume 20, Issue 3, Pages 1738-1746Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.nanolett.9b04957
Keywords
Anti-inflammation therapy; pulmonary siRNA delivery; mucus permeation; cell penetration; helical polypeptide; fluorination
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Funding
- Ministry of Science and Technology of China [2016YFA0201200]
- National Natural Science Foundation of China [51573123, 51722305, 51873142]
- 111 project
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
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The mucus layer and cell membrane are two major barriers against pulmonary siRNA delivery. Commonly used polycationic gene vectors can hardly penetrate the mucus layer due to the adsorption of mucin glycoproteins that trap and destabilize the polyplexes. Herein, guanidinated and fluorinated bifunctional helical polypeptides were developed to synchronizingly overcome these two barriers. The guanidine domain and alpha-helix facilitated trans-membrane siRNA delivery into macrophages, whereas fluorination of the polypeptides dramatically enhanced the mucus permeation capability by similar to 240 folds, because incorporated fluorocarbon segments prevented adsorption of mucin glycoproteins onto polyplexes surfaces. Thus, when delivering TNF-alpha siRNA intratracheally, the topperforming polypeptide P7F7 provoked highly efficient gene knockdown by similar to 96% at 200 mu g/kg siRNA and exerted pronounced anti-inflammatory effect against acute lung injury. This study thus provides an effective strategy for transmucosal gene delivery, and it also renders promising utilities for the noninvasive, localized treatment of inflammatory pulmonary diseases.
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