Ionizable polymeric micelles (IPMs) for efficient siRNA delivery

被引：6

作者：

Zhou, Ziyu ^{[1
,2
]}

Feng, Yu ^{[1
]}

Jiang, Mingzhou ^{[3
]}

Yao, Zijun ^{[1
]}

Wang, Jing ^{[1
]}

Pan, Feng ^{[4
,5
]}

Feng, Rulan ^{[1
]}

Zhao, Chong ^{[1
]}

Ma, Yinyu ^{[6
,7
]}

Zhou, Jinge ^{[8
]}

Sun, Lei ^{[1
,9
]}

Sun, Xiaotian ^{[3
]}

Zhan, Changyou ^{[4
,5
,6
,7
]}

He, Xiao ^{[1
,10
]}

Jiang, Kuan ^{[6
,7
,11
,12
]}

Yu, Jiahui ^{[1
]}

Yan, Zhiqiang ^{[1
,10
]}

机构：

[1] East China Normal Univ, Inst Biomed Engn & Technol, Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev, Sch Chem & Mol Engn, Shanghai, Peoples R China

[2] East China Normal Univ, Sch Pharm, Shanghai, Peoples R China

[3] Fudan Univ, HuaShan Hosp, Dept Cardiothorac Surg, Shanghai, Peoples R China

[4] Shanghai Fudan Univ, Sch Pharm, Key Lab Smart Drug Delivery, Minist Educ, Shanghai, Peoples R China

[5] Shanghai Fudan Univ, Sch Pharm, Dept Pharm, Key Lab Smart Drug Delivery, Shanghai, Peoples R China

[6] Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai, Peoples R China

[7] Fudan Univ, State Key Lab Mol Engn Polymers, Shanghai, Peoples R China

[8] Kunming Med Univ, Inst Biomed Engn, Kunming, Peoples R China

[9] Univ Calif San Diego, Dept Nanoengn, Chem Engn Program, La Jolla, CA USA

[10] East China Normal Univ, Shanghai Frontiers Sci Ctr Mol Intelligent Synth, Sch Chem & Mol Engn, Shanghai, Peoples R China

[11] Fudan Univ, Eye & ENT Hosp, Eye Inst, Shanghai, Peoples R China

[12] Fudan Univ, Eye & ENT Hosp, Dept Ophthalmol, Shanghai, Peoples R China

来源：

NATURE COMMUNICATIONS | 2025年 / 16卷 / 01期

基金：

国家重点研发计划; 中国国家自然科学基金;

关键词：

LIPID NANOPARTICLES; MULTICENTER; PACLITAXEL; HSC;

D O I：

10.1038/s41467-024-55721-w

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Lipid nanoparticles (LNPs) are widely used for nucleic acid delivery but face challenges like limited targeting and accelerated blood clearance (ABC) effect. We design three ionizable oligomers (IOs) that, with polylactide-polyethylene glycol (PLA-PEG), form a potential siRNA delivery system, named Ionizable Polymeric Micelles (IPMs). The siRNA encapsulated IPMs escape from lysosomes upon cellular uptake, and silence the target gene. A fibroblast activation protein inhibitor modified IPMs (FAPi-IPMs) show higher targeting for activated hepatic stellate cells (HSCs) compared to that for hepatocytes, silencing both HSP47 and HMGB1, reducing collagen secretion and liver inflammation, thereby treating fibrosis. Moreover, IPMs and FAPi-IPMs mitigate ABC effect and produce fewer PEG antibodies than LNPs, and show minimal apolipoprotein adsorption in vivo compared with LNPs, differentiating their targeting effects from LNPs. In conclusion, IPMs represent a nucleic acid delivery system with alternative targeting ability and reduced ABC effect.

引用

页数：15

共 62 条

[41] Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine [J].

Polack, Fernando P. ;

Thomas, Stephen J. ;

Kitchin, Nicholas ;

Absalon, Judith ;

Gurtman, Alejandra ;

Lockhart, Stephen ;

Perez, John L. ;

Perez Marc, Gonzalo ;

Moreira, Edson D. ;

Zerbini, Cristiano ;

Bailey, Ruth ;

Swanson, Kena A. ;

Roychoudhury, Satrajit ;

Koury, Kenneth ;

Li, Ping ;

Kalina, Warren V. ;

Cooper, David ;

Frenck, Robert W., Jr. ;

Hammitt, Laura L. ;

Tureci, Ozlem ;

Nell, Haylene ;

Schaefer, Axel ;

Unal, Serhat ;

Tresnan, Dina B. ;

Mather, Susan ;

Dormitzer, Philip R. ;

Sahin, Ugur ;

Jansen, Kathrin U. ;

Gruber, William C. .

NEW ENGLAND JOURNAL OF MEDICINE, 2020, 383 (27) :2603-2615

[42] Lung-selective mRNA delivery of synthetic lipid nanoparticles for the treatment of pulmonary lymphangioleiomyomatosis [J].

Qiu, Min ;

Tang, Yan ;

Chen, Jinjin ;

Muriph, Rachel ;

Ye, Zhongfeng ;

Huang, Changfeng ;

Evans, Jason ;

Henske, Elizabeth P. ;

Xu, Qiaobing .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2022, 119 (08)

[43] Peptide-encoding mRNA barcodes for the high-throughput in vivo screening of libraries of lipid nanoparticles for mRNA delivery [J].

Rhym, Luke H. ;

Manan, Rajith S. ;

Koller, Antonius ;

Stephanie, Georgina ;

Anderson, Daniel G. .

NATURE BIOMEDICAL ENGINEERING, 2023, 7 (07) :901-+

[44] Augmented lipid-nanoparticle-mediated in vivo genome editing in the lungs and spleen by disrupting Cas9 activity in the liver [J].

Sago, Cory D. ;

Lokugamage, Melissa P. ;

Loughrey, David ;

Lindsay, Kevin E. ;

Hincapie, Robert ;

Krupczak, Brandon R. ;

Kalathoor, Sujay ;

Sato, Manaka ;

Echeverri, Elisa Schrader ;

Fitzgerald, Jordan P. ;

Gan, Zubao ;

Gamboa, Lena ;

Paunovska, Kalina ;

Sanhueza, Carlos A. ;

Hatit, Marine Z. C. ;

Finn, M. G. ;

Santangelo, Philip J. ;

Dahlman, James E. .

NATURE BIOMEDICAL ENGINEERING, 2022, 6 (02) :157-+

[45] Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone [J].

Sato, Yasushi ;

Murase, Kazuyuki ;

Kato, Junji ;

Kobune, Masayoshi ;

Sato, Tsutomu ;

Kawano, Yutaka ;

Takimoto, Rishu ;

Takada, Kouichi ;

Miyanishi, Koji ;

Matsunaga, Takuya ;

Takayama, Tetsuji ;

Niitsu, Yoshiro .

NATURE BIOTECHNOLOGY, 2008, 26 (04) :431-442

[46] Different kinetics for the hepatic uptake of lipid nanoparticles between the apolipoprotein E/low density lipoprotein receptor and the N-acetyl-D-galactosamine/asialoglycoprotein receptor pathway [J].

Sato, Yusuke ;

Kinami, Yoshiyuki ;

Hashiba, Kazuki ;

Harashima, Hideyoshi .

JOURNAL OF CONTROLLED RELEASE, 2020, 322 :217-226

[47] Rational design of cationic lipids for siRNA delivery [J].

Semple, Sean C. ;

Akinc, Akin ;

Chen, Jianxin ;

Sandhu, Ammen P. ;

Mui, Barbara L. ;

Cho, Connie K. ;

Sah, Dinah W. Y. ;

Stebbing, Derrick ;

Crosley, Erin J. ;

Yaworski, Ed ;

Hafez, Ismail M. ;

Dorkin, J. Robert ;

Qin, June ;

Lam, Kieu ;

Rajeev, Kallanthottathil G. ;

Wong, Kim F. ;

Jeffs, Lloyd B. ;

Nechev, Lubomir ;

Eisenhardt, Merete L. ;

Jayaraman, Muthusamy ;

Kazem, Mikameh ;

Maier, Martin A. ;

Srinivasulu, Masuna ;

Weinstein, Michael J. ;

Chen, Qingmin ;

Alvarez, Rene ;

Barros, Scott A. ;

De, Soma ;

Klimuk, Sandra K. ;

Borland, Todd ;

Kosovrasti, Verbena ;

Cantley, William L. ;

Tam, Ying K. ;

Manoharan, Muthiah ;

Ciufolini, Marco A. ;

Tracy, Mark A. ;

de Fougerolles, Antonin ;

MacLachlan, Ian ;

Cullis, Pieter R. ;

Madden, Thomas D. ;

Hope, Michael J. .

NATURE BIOTECHNOLOGY, 2010, 28 (02) :172-U18

[48] Comparing nanoparticle polymeric micellar paclitaxel and solvent-based paclitaxel as first-line treatment of advanced non-small-cell lung cancer: an open-label, randomized, multicenter, phase III trial [J].

Shi, M. ;

Gu, A. ;

Tu, H. ;

Huang, C. ;

Wang, H. ;

Yu, Z. ;

Wang, X. ;

Cao, L. ;

Shu, Y. ;

Yang, R. ;

Li, X. ;

Chang, J. ;

Hu, Y. ;

Shen, P. ;

Guo, Z. ;

Tao, M. ;

Zhang, Y. ;

Liu, X. ;

Sun, Q. ;

Zhang, X. ;

Jiang, Z. ;

Zhao, J. ;

Chen, F. ;

Yu, H. ;

Zhang, W. ;

Sun, J. ;

Li, D. ;

Zhou, J. ;

Han, B. ;

Wu, Y. L. .

ANNALS OF ONCOLOGY, 2021, 32 (01) :85-96

[49] Targeting hepatic macrophages to treat liver diseases [J].

Tacke, Frank .

JOURNAL OF HEPATOLOGY, 2017, 66 (06) :1300-1312

[50] Fibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis [J].

Tsuchiya, Yuichi ;

Seki, Takao ;

Kobayashi, Kenta ;

Komazawa-Sakon, Sachiko ;

Shichino, Shigeyuki ;

Nishina, Takashi ;

Fukuhara, Kyoko ;

Ikejima, Kenichi ;

Nagai, Hidenari ;

Igarashi, Yoshinori ;

Ueha, Satoshi ;

Oikawa, Akira ;

Tsurusaki, Shinya ;

Yamazaki, Soh ;

Nishiyama, Chiharu ;

Mikami, Tetuo ;

Yagita, Hideo ;

Okumura, Ko ;

Kido, Taketomo ;

Miyajima, Atsushi ;

Matsushima, Kouji ;

Imasaka, Mai ;

Araki, Kimi ;

Imamura, Toru ;

Ohmuraya, Masaki ;

Tanaka, Minoru ;

Nakano, Hiroyasu .

NATURE COMMUNICATIONS, 2023, 14 (01)

← 1 2 3 4 5 6 7 →