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Treatment of Ulcerative Colitis by Cationic Liposome Delivered NLRP3 siRNA

PURPOSE: The abnormal activation of NLRP3 inflammasome is related to the occurrence and development of ulcerative colitis (UC). However, the ideal drug and delivery system remain important factors limiting the targeting of NLRP3 inflammasome in UC therapy. Gene therapy by delivering siRNA is effecti...

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Autores principales: Huang, Jing, Dai, Mengmeng, He, Mingxia, Bu, Weicheng, Cao, Liwen, Jing, Jing, Cao, Run, Zhang, Hailong, Men, Ke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440093/
https://www.ncbi.nlm.nih.gov/pubmed/37605735
http://dx.doi.org/10.2147/IJN.S413149
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author Huang, Jing
Dai, Mengmeng
He, Mingxia
Bu, Weicheng
Cao, Liwen
Jing, Jing
Cao, Run
Zhang, Hailong
Men, Ke
author_facet Huang, Jing
Dai, Mengmeng
He, Mingxia
Bu, Weicheng
Cao, Liwen
Jing, Jing
Cao, Run
Zhang, Hailong
Men, Ke
author_sort Huang, Jing
collection PubMed
description PURPOSE: The abnormal activation of NLRP3 inflammasome is related to the occurrence and development of ulcerative colitis (UC). However, the ideal drug and delivery system remain important factors limiting the targeting of NLRP3 inflammasome in UC therapy. Gene therapy by delivering siRNA is effective in treating various diseases. Therefore, delivering siNLRP3 using an ideal vector for UC treatment is necessary. MATERIALS AND METHODS: Nanoparticles delivering siNLRP3 were developed based on cationic liposome (CLP/siNLRP3). Their ability to inhibit NLRP3 inflammasome activation was monitored using Western blot (WB) and Enzyme-linked Immunosorbent Assay (ELISA). The ASC oligomerization in LPS-primed peritoneal macrophages (PMs) was detected by WB and immunofluorescence. Moreover, we assessed the role of CLP/siNLRP3 on dextran sodium sulfate (DSS)-induced UC by examining NLRP3 levels, pro-inflammatory cytokines expression, and disease-associated index (DAI). Flow cytometry (FCM) was used to detect the contents of macrophages and T cells. Finally, we assessed the safety of CLP/siNLRP3. RESULTS: The prepared CLP was spherical, with a small particle size (94 nm) and low permeability. The CLP could efficiently protect siNLRP3 from degradation and then deliver siNLRP3 into PMs, inhibiting NLRP3 inflammasome activation. Also, the CLP/siNLRP3 could inhibit the secretion of mature IL-1β and IL-18 from PMs, thereby achieving a favorable anti-inflammation effect. In vivo, CLP/siNLRP3 could effectively alleviate intestinal injury in UC mice, which was attributed to down-regulating levels of IL-1β and IL-18, inhibiting infiltration of macrophages and other immune cells, and the polarization of M1 macrophages. Finally, pathological testing of tissue sections and blood biochemical tests showed no significant toxic effects of CLP/siNLRP3. CONCLUSION: We introduced a prospective approach for the efficient delivery of siRNA in vitro and in vivo with high safety and stability, which was found to have great potential in treating NLRP3-driven diseases in an RNA-silencing manner.
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spelling pubmed-104400932023-08-21 Treatment of Ulcerative Colitis by Cationic Liposome Delivered NLRP3 siRNA Huang, Jing Dai, Mengmeng He, Mingxia Bu, Weicheng Cao, Liwen Jing, Jing Cao, Run Zhang, Hailong Men, Ke Int J Nanomedicine Original Research PURPOSE: The abnormal activation of NLRP3 inflammasome is related to the occurrence and development of ulcerative colitis (UC). However, the ideal drug and delivery system remain important factors limiting the targeting of NLRP3 inflammasome in UC therapy. Gene therapy by delivering siRNA is effective in treating various diseases. Therefore, delivering siNLRP3 using an ideal vector for UC treatment is necessary. MATERIALS AND METHODS: Nanoparticles delivering siNLRP3 were developed based on cationic liposome (CLP/siNLRP3). Their ability to inhibit NLRP3 inflammasome activation was monitored using Western blot (WB) and Enzyme-linked Immunosorbent Assay (ELISA). The ASC oligomerization in LPS-primed peritoneal macrophages (PMs) was detected by WB and immunofluorescence. Moreover, we assessed the role of CLP/siNLRP3 on dextran sodium sulfate (DSS)-induced UC by examining NLRP3 levels, pro-inflammatory cytokines expression, and disease-associated index (DAI). Flow cytometry (FCM) was used to detect the contents of macrophages and T cells. Finally, we assessed the safety of CLP/siNLRP3. RESULTS: The prepared CLP was spherical, with a small particle size (94 nm) and low permeability. The CLP could efficiently protect siNLRP3 from degradation and then deliver siNLRP3 into PMs, inhibiting NLRP3 inflammasome activation. Also, the CLP/siNLRP3 could inhibit the secretion of mature IL-1β and IL-18 from PMs, thereby achieving a favorable anti-inflammation effect. In vivo, CLP/siNLRP3 could effectively alleviate intestinal injury in UC mice, which was attributed to down-regulating levels of IL-1β and IL-18, inhibiting infiltration of macrophages and other immune cells, and the polarization of M1 macrophages. Finally, pathological testing of tissue sections and blood biochemical tests showed no significant toxic effects of CLP/siNLRP3. CONCLUSION: We introduced a prospective approach for the efficient delivery of siRNA in vitro and in vivo with high safety and stability, which was found to have great potential in treating NLRP3-driven diseases in an RNA-silencing manner. Dove 2023-08-16 /pmc/articles/PMC10440093/ /pubmed/37605735 http://dx.doi.org/10.2147/IJN.S413149 Text en © 2023 Huang et al. https://creativecommons.org/licenses/by-nc/3.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/ (https://creativecommons.org/licenses/by-nc/3.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Huang, Jing
Dai, Mengmeng
He, Mingxia
Bu, Weicheng
Cao, Liwen
Jing, Jing
Cao, Run
Zhang, Hailong
Men, Ke
Treatment of Ulcerative Colitis by Cationic Liposome Delivered NLRP3 siRNA
title Treatment of Ulcerative Colitis by Cationic Liposome Delivered NLRP3 siRNA
title_full Treatment of Ulcerative Colitis by Cationic Liposome Delivered NLRP3 siRNA
title_fullStr Treatment of Ulcerative Colitis by Cationic Liposome Delivered NLRP3 siRNA
title_full_unstemmed Treatment of Ulcerative Colitis by Cationic Liposome Delivered NLRP3 siRNA
title_short Treatment of Ulcerative Colitis by Cationic Liposome Delivered NLRP3 siRNA
title_sort treatment of ulcerative colitis by cationic liposome delivered nlrp3 sirna
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440093/
https://www.ncbi.nlm.nih.gov/pubmed/37605735
http://dx.doi.org/10.2147/IJN.S413149
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