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Endoplasmic reticulum-targeted delivery of celastrol and PD-L1 siRNA for reinforcing immunogenic cell death and potentiating cancer immunotherapy

文献类型：期刊论文

作者Wang, Jie4,5; Zhang, Zilong4,5; Zhuo, Yan3,4; Zhang, Zhuan2; Chen, Rongrong2; Liang, Li2; Jiang, Xiaohe4,6; Nie, Di4; Liu, Chang4,6; Zou, Zhiwen4
刊名ACTA PHARMACEUTICA SINICA B
出版日期2024-08-01
卷号14期号:8页码:3643-3660
关键词Chemoimmunotherapy Targeted drug delivery Endoplasmic reticulum Endoplasmic reticulum stress Immunogenic cell death siRNA Exosomes Colorectal cancer
ISSN号2211-3835
DOI10.1016/j.apsb.2024.04.010
通讯作者Wang, Rui(ellewang@163.com) ; Gan, Yong(ygan@simm.ac.cn) ; Yu, Miaorong(mryu@simm.ac.cn)
英文摘要The prospect of employing chemoimmunotherapy targeted towards the endoplasmic reticulum (ER) presents an opportunity to amplify the synergistic effects of chemotherapy and immunotherapy. In this study, we initially validated celastrol (CEL) as an inducer of immunogenic cell death (ICD) by promoting ER stress and autophagy in colorectal cancer (CRC) cells. Subsequently, an ER-targeted strategy was posited, involving the codelivery of CEL with PD-L1 small interfering RNAs (siRNA) using KDEL peptide-modified exosomes derived from milk (KME), to enhance chemoimmunotherapy outcomes. Our findings demonstrate the efficient transportation of KME to the ER via the Golgi-to-ER pathway. Compared to their non-targeting counterparts, KME exhibited a significant augmentation of the CEL-induced ICD effect. Additionally, it facilitated the release of danger signaling molecules (DAMPs), thereby stimulating the antigen-presenting function of dendritic cells and promoting the infiltration of T cells into the tumor. Concurrently, the ER-targeted delivery of PD-L1 siRNA resulted in the downregulation of both intracellular and membrane PD-L1 protein expression, consequently fostering the proliferation and activity of CD8+ + T cells. Ultimately, the ER-targeted formulation exhibited enhanced anti-tumor efficacy and provoked anti-tumor immune responses against orthotopic colorectal tumors in vivo. . Collectively, a robust ER-targeted delivery strategy provides an encouraging approach for achieving potent cancer chemoimmunotherapy. 2024 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
WOS关键词BLOCKADE
资助项目National Science Fund of Distinguished Young Scholars (China)[82025032] ; National Natural Science Foundation of China (China)[82073773] ; Key Research Program of Chinese Academy of Sciences (China)[ZDBS-ZRKJZ-TLC005] ; Open Competition to Select the Best Candidates Key Technology Program for Nucleic Acid Drugs of NCTIB (China)[NCTIB2022HS01006] ; Young Elite Scientists Sponsorship Program by CAST (China)[2022QNRC001] ; Shanghai Action Plan for Science, Technology, and Innovation (China)[23HC1401200] ; Shanghai Post-doctoral Excellence Program (China)[2022693] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences (China)[SIMM0220232001]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001293049200001
出版者INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/312809]  
专题新药研究国家重点实验室
通讯作者Wang, Rui; Gan, Yong; Yu, Miaorong
作者单位1.Natl Inst Food & Drug Control, NMPA Key Lab Qual Res & Evaluat Pharmaceut Excipie, Beijing 100050, Peoples R China
2.Nanjing Univ Chinese Med, Sch Pharm, Nanjing 210023, Peoples R China
3.Nanchang Univ, Jiangxi Med Coll, Nanchang 330006, Peoples R China
4.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
5.Shanghai Univ Tradit Chinese Med, Sch Pharm, Shanghai 201203, Peoples R China
6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Jie,Zhang, Zilong,Zhuo, Yan,et al. Endoplasmic reticulum-targeted delivery of celastrol and PD-L1 siRNA for reinforcing immunogenic cell death and potentiating cancer immunotherapy[J]. ACTA PHARMACEUTICA SINICA B,2024,14(8):3643-3660.
APA Wang, Jie.,Zhang, Zilong.,Zhuo, Yan.,Zhang, Zhuan.,Chen, Rongrong.,...&Yu, Miaorong.(2024).Endoplasmic reticulum-targeted delivery of celastrol and PD-L1 siRNA for reinforcing immunogenic cell death and potentiating cancer immunotherapy.ACTA PHARMACEUTICA SINICA B,14(8),3643-3660.
MLA Wang, Jie,et al."Endoplasmic reticulum-targeted delivery of celastrol and PD-L1 siRNA for reinforcing immunogenic cell death and potentiating cancer immunotherapy".ACTA PHARMACEUTICA SINICA B 14.8(2024):3643-3660.

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来源：上海药物研究所

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