TY - JOUR

T1 - Airway epithelial cell-specific delivery of lipid nanoparticles loading siRNA for asthma treatment

AU - Zhang, Mengjun

AU - Jiang, Huiyang

AU - Wu, Lan

AU - Lu, Haoyu

AU - Bera, Hriday

AU - Zhao, Xing

AU - Guo, Xiong

AU - Liu, Xulu

AU - Cun, Dongmei

AU - Yang, Mingshi

N1 - Funding Information: This work was financially supported by the Liaoning Pan Deng Xue Zhe Scholar (No. XLYC2002061), the National Natural Science Foundation of China (No. 82173768), and the Overseas Expertise Introduction Project for Discipline Innovation (“111 Project”) (No. D20029). L.W. acknowledges the financial supports from National Natural Science Foundation of China, Govt. of China (grant No. 82204316) and China Postdoctoral Science Foundation, Govt. of China (grant No. 2021TQ0219 and 2022MD713776). H.B. thanks the financial support from National Natural Science Foundation of China, Govt. of China (grant No. 81850410554 and 82050410448) and Fellowship of China Postdoctoral Science Foundation, Govt. of China (grant No. 2021MD703857). X.G. acknowledges the 2021 annual scientific research funding project of the Educational Department of Liaoning Province (grant No. LJKZ0925) and higher education institutions fundamental scientific research project of the Educational Department of Liaoning Province (Youth Project, grant No. LJKQZ2021035). D.C. acknowledges financial support from Provincial Natural Science Foundation Project of Liaoning (NO. 2022-MS-241), General program of Provincial Department of Education of Liaoning (NO. LJKZ0951) and Liaoning Xingliao Young Top Talent (NO. XLYC1907042). Funding Information: This work was financially supported by the Liaoning Pan Deng Xue Zhe Scholar (No. XLYC2002061), the National Natural Science Foundation of China (No. 82173768), and the Overseas Expertise Introduction Project for Discipline Innovation (“111 Project”) (No. D20029 ). L.W. acknowledges the financial supports from National Natural Science Foundation of China , Govt. of China (grant No. 82204316) and China Postdoctoral Science Foundation, Govt. of China (grant No. 2021TQ0219 and 2022MD713776 ). H.B. thanks the financial support from National Natural Science Foundation of China , Govt. of China (grant No. 81850410554 and 82050410448 ) and Fellowship of China Postdoctoral Science Foundation, Govt. of China (grant No. 2021MD703857 ). X.G. acknowledges the 2021 annual scientific research funding project of the Educational Department of Liaoning Province (grant No. LJKZ0925 ) and higher education institutions fundamental scientific research project of the Educational Department of Liaoning Province (Youth Project, grant No. LJKQZ2021035 ). D.C. acknowledges financial support from Provincial Natural Science Foundation Project of Liaoning (NO. 2022-MS-241 ), General program of Provincial Department of Education of Liaoning (NO. LJKZ0951 ) and Liaoning Xingliao Young Top Talent (NO. XLYC1907042 ). Publisher Copyright: © 2022 Elsevier B.V.

PY - 2022

Y1 - 2022

N2 - 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 proinflammatory 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.

AB - 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 proinflammatory 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.

KW - Airway epithelial cells

KW - Asthma

KW - Lipid nanoparticles

KW - Pulmonary delivery

KW - siRNA

U2 - 10.1016/j.jconrel.2022.10.020

DO - 10.1016/j.jconrel.2022.10.020

M3 - Journal article

C2 - 36265740

AN - SCOPUS:85140909122

VL - 352

SP - 422

EP - 437

JO - Journal of Controlled Release

JF - Journal of Controlled Release

SN - 0168-3659

ER -