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

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外文摘要：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.

外文关键词：

ChemoimmunotherapyTargeted drug deliveryEndoplasmic reticulumEndoplasmic reticulum stressImmunogenic cell deathsiRNAExosomesColorectal cancer

作者：

Jie Wang、Zilong Zhang、Yan Zhuo、Zhuan Zhang、Rongrong Chen、Li Liang、Xiaohe Jiang、Di Nie、Chang Liu、Zhiwen Zou、Xiang Li、Jiaxin Li、Bingqi Wang、Rui Wang、Yong Gan、Miaorong Yu

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作者单位：

School of Pharmacy,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China

State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China

Jiangxi Medical College,Nanchang University,Nanchang 330006,China

School of Pharmacy,Nanjing University of Chinese Medicine,Nanjing 210023,China

University of Chinese Academy of Sciences,Beijing 100049,China

NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients,National Institutes for Food and Drug Control,Beijing 100050,China

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基金：

National Science Fund of Distinguished Young Scholars,ChinaNational Natural Science Foundation of ChinaKey Research Program of Chinese Academy of Sciences,Chinathe"Open Competition to Select the Best Candidates"Key Technology Program for Nucleic Acid Drugs of NCTIB,ChinaYoung Elite Scientists Sponsorship Program by CAST,ChinaShanghai Action Plan for Science,Technology,and Innovation,ChinaShanghai Postdoctoral Excellence Program,ChinaShanghai Institute of Materia Medica,Chinese Academy of Sciences,China

项目编号：

8202503282073773ZDBS-ZRKJZ-TLC005NCTIB2022HS010062022QNRC00123HC14012002022693SIMM0220232001

出版年：

2024

DOI：

10.1016/j.apsb.2024.04.010

药学学报(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.14(8)