ROS-sensitive PD-L1 siRNA cationic selenide nanogels for self-inhibition of autophagy and prevention of immune escape  

作　　者：Jie Gao Yonghua Zhai Weihong Lu Xianghe Jiang Jingsheng Zhou Lili Wu Longhai Du Chunqing Ou Xinyi Zhang Hanliang He Jian Zhu Zhengbiao Zhang Meiyun Li Yan Wu Xiangqiang Pan 

机构地区：[1]State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials,Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application,College of Chemistry,Chemical Engineering and Materials Science,Soochow University,Suzhou,215123,China [2]Changhai Clinical Research Unit,Shanghai Changhai Hospital,Naval Medical University,Shanghai,200433,China [3]Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices,Shanghai,200433,China [4]College of Life Science,Mudanjiang Medical University,Mudanjiang,157011,China [5]Department of Orthopedics,Jinshan Hospital,Fudan University,Shanghai,201508,China [6]The Department of Orthopedic Surgery,Dushu Lake Hospital Affiliated to Soochow University,Suzhou,215028,China

出　　处：《Bioactive Materials》2024年第11期597-610,共14页生物活性材料（英文）

基　　金：National Natural Science Foundation of China(No.21971177,82072051);Natural Science Foundation of the Jiangsu Higher Education Institution of China(No.22KJA150004);Priority Academic Program Development(PAPD)of Jiangsu Higher Education Institutions;Jiangsu Key Laboratory of Advanced Functional Polymers Design and Application,Soochow University;Suzhou Key Laboratory of Macromolecular Design and Precision Synthesis and the Program of Innovative Research Team of Soochow University.

摘　　要：In the field of cancer therapy,inhibiting autophagy has emerged as a promising strategy.However,pharmacological disruption of autophagy can lead to the upregulation of programmed death-ligand 1(PD-L1),enabling tumor immune evasion.To address this issue,we developed innovative ROS-responsive cationic poly(ethylene imine)(PEI)nanogels using selenol chemistry-mediated multicomponent reaction(MCR)technology.This procedure involved simple mixing of low-molecular-weight PEI(LMW PEI),γ-selenobutylacetone(γ-SBL),and poly(ethylene glycol)methacrylate(PEGMA).Through high-throughput screening,we constructed a library of AxSeyOz nanogels and identified the optimized A1.8Se3O0.5/siPD-L1 nanogels,which exhibited a size of approximately 200 nm,excellent colloidal stability,and the most effective PD-L1 silencing efficacy.These nanogels demonstrated enhanced uptake by tumor cells,excellent oxidative degradation ability,and inhibited autophagy by alkalinizing lysosomes.The A1.8Se3O0.5/siPD-L1 nanogels significantly downregulated PD-L1 expression and increased the expression of major histocompatibility complex class I(MHC-I),resulting in robust proliferation of specific CD8+T cells and a decrease in MC38 tumor growth.As a result,the A1.8Se3O0.5/siPD-L1 nanogels inhibited tumor growth through self-inhibition of autophagy,upregulation of MHC-I,and downregulation of PD-L1.Designed with dynamic diselenide bonds,the A1.8Se3O0.5/siPD-L1 nanogels showed synergistic antitumor efficacy through self-inhibition of autophagy and prevention of immune escape.

关 键 词：Multicomponent reaction ROS sensitive Cationic nanogel Autophagy inhibition Immune escape 

分 类 号：TQ427.2[化学工程]