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

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 

机构地区：[1]School of Pharmacy,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China [2]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [3]Jiangxi Medical College,Nanchang University,Nanchang 330006,China [4]School of Pharmacy,Nanjing University of Chinese Medicine,Nanjing 210023,China [5]University of Chinese Academy of Sciences,Beijing 100049,China [6]NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients,National Institutes for Food and Drug Control,Beijing 100050,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第8期3643-3660,共18页药学学报（英文版）

基　　金：the financial support from the National Science Fund of Distinguished Young Scholars(No.82025032,China);the National Natural Science Foundation of China(No.82073773,China);the Key Research Program of Chinese Academy of Sciences(No.ZDBS-ZRKJZ-TLC005,China);the"Open Competition to Select the Best Candidates"Key Technology Program for Nucleic Acid Drugs of NCTIB(No.NCTIB2022HS01006,China);Young Elite Scientists Sponsorship Program by CAST(No.2022QNRC001,China);Shanghai Action Plan for Science,Technology,and Innovation(No.23HC1401200,China);Shanghai Post-doctoral Excellence Program(No.2022693,China);Shanghai Institute of Materia Medica,Chinese Academy of Sciences(No.SIMM0220232001,China).

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.

关 键 词：CHEMOIMMUNOTHERAPY Targeted drug delivery Endoplasmic reticulum Endoplasmic reticulum stress Immunogenic cell death SIRNA CHEMOIMMUNOTHERAPY Targeted drug delivery Endoplasmic reticulum Endoplasmic reticulum stress Immunogenic cell death SIRNA 

分 类 号：R730.51[医药卫生—肿瘤]