4.8 Article

Airway epithelial cell-specific delivery of lipid nanoparticles loading siRNA for asthma treatment

Journal

JOURNAL OF CONTROLLED RELEASE
Volume 352, Issue -, Pages 422-437

Publisher

ELSEVIER
DOI: 10.1016/j.jconrel.2022.10.020

Keywords

Pulmonary delivery; siRNA; Lipid nanoparticles; Asthma; Airway epithelial cells

Funding

  1. Liaoning Pan Deng Xue Zhe Scholar [XLYC2002061]
  2. National Natural Science Foundation of China [82173768]
  3. Overseas Expertise Introduc-tion Project for Discipline Innovation
  4. Overseas Expertise Introduction Project for Discipline Innovation (111 Project)
  5. National Natural Science Foundation of China, Govt. of China
  6. China Postdoctoral Science Foundation, Govt. of China [2022MD713776]
  7. Fellowship of China Postdoctoral Science Foundation, Govt. of China [81850410554]
  8. the 2021 annual scientific research funding project of the Educational Department of Liaoning Province [82050410448, 2021MD703857, LJKZ0925, LJKQZ2021035]
  9. higher education institutions fundamental scientific research project of the Educational Department of Liaoning Province [2022-MS-241]
  10. Provincial Natural Science Foundation Project of Liaoning [LJKZ0951]
  11. General program of Provincial Department of Education of Liaoning [XLYC1907042]
  12. Liaoning Xingliao Young Top Talent
  13. [D20029]
  14. [82204316]
  15. [2021TQ0219]

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This study demonstrates the successful delivery of siRNA to AECs using inhaled lipid nanoparticles (LNPs) targeting ICAM-1 receptors, resulting in reduced expression of proinflammatory cytokines in AECs and effective alleviation of symptoms in asthmatic mice.
With specific and inherent mRNA cleaving activity, small interfering RNA (siRNA) has been deemed promising therapeutics to reduce the exacerbation rate of asthma by inhibiting the expression and release of proin-flammatory cytokines from airway epithelial cells (AECs). To exert the therapeutic effects of siRNA drugs, nano -formulations with high efficiency and safety are required to deliver these nucleic acids to the target cells. Herein, we exploited novel inhaled lipid nanoparticles (LNPs) targeting intercellular adhesion molecule-1 (ICAM-1) receptors on the apical side of AECs. This delivery system is meant to enhance the specific delivery efficiency of siRNA in AECs to prevent the expression of proinflammatory cytokines in AECs and the concomitant symptoms in parallel. A cyclic peptide that resembles part of the capsid protein of rhinovirus and binds to ICAM-1 receptors was initially conjugated with cholesterol and subsequently assembled with ionizable cationic lipids to form the LNPs (Pep-LNPs) loaded with siRNA against thymic stromal lymphopoietin (TSLP siRNA). The obtained Pep-LNPs were subjected to thorough characterization and evaluations in vitro and in vivo. Pep-LNPs significantly enhanced cellular uptake and gene silencing efficiency in human epithelial cells expressing ICAM-1 in vitro, exhibited AEC-specific delivery and improved the gene silencing effect in ovalbumin-challenged asthmatic mice after pulmonary administration. More importantly, Pep-LNPs remarkably downregulated the expression of TSLP in AECs, effectively alleviated inflammatory cell infiltration, and reduced the secretion of other proinflammatory cytokines, including IL-4 and IL-13, as well as mucus production in asthmatic mice. This study demonstrates that Pep-LNPs are safe and efficient to deliver siRNA drugs to asthmatic AECs and could potentially alleviate allergic asthma by inhibiting the overexpression of proinflammatory cytokines in the airway.

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