Glutathione-responsive nanoplatform for intra/extracellular lactate exhaustion to enhance antitumor immunotherapy

作者全名："Tan, Yandi; Huang, Ju; Zhang, Liang; Tang, Xinyi; Zhang, Chunmei; Xiang, Hongwei; Shen, Bin; Zheng, Jun; Leng, Xiaojing; Li, Rui"

作者地址："[Tan, Yandi; Huang, Ju; Tang, Xinyi; Zhang, Chunmei; Xiang, Hongwei; Shen, Bin; Li, Rui] Chongqing Med Univ, Dept Ultrasonog, Affiliated Hosp 3, Chongqing 401120, Peoples R China; [Zhang, Liang] Chongqing Med Univ, Ultrasound Dept, Affiliated Hosp 1, Chongqing 400010, Peoples R China; [Zhang, Liang; Zheng, Jun; Leng, Xiaojing] Chongqing Med Univ, Chongqing Key Lab Ultrasound Mol Imaging & Inst Ul, Affiliated Hosp 2, Chongqing 400016, Peoples R China"

通信作者："Li, R (通讯作者)，Chongqing Med Univ, Dept Ultrasonog, Affiliated Hosp 3, Chongqing 401120, Peoples R China."

来源：MATERIALS & DESIGN

ESI学科分类：MATERIALS SCIENCE

WOS号：WOS:000990134600001

JCR分区：Q1

影响因子：7.6

年份：2023

卷号：227

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Glutathione-responsive hollow mesoporous; organosilicon; Lactate; Immunosuppressive tumor; microenvironment; Immunotherapy; Nanomedicine

摘要："Despite the critical breakthrough achieved by immune checkpoint blockade (ICB) therapies in the clinic, the antitumor effect is seriously restricted by the immunosuppressive tumor microenvironment (ITM). A variety of strategies to alleviate the ITM have been investigated. Direct regulation of lactate metabolism in the tumor microenvironment (TME) holds promise for ITM modulation. Herein, we fabricated a glutathione-responsive PEGylated hollow mesoporous organosilicon (HMOP), with monocarboxylate transporter 1/4 inhibitor (diclofenac, DC) and lactate oxidase (LOX) loaded in/onto the HMOP (denoted as DC-HMOP-LOX). DC-HMOP-LOX could spontaneously be biodegraded in the TME due to the disulfide bonds, and then DC/LOX could be released to exhaust intra/extracellular lactate. DC-HMOP-LOX hindered the transmission of lactate effectively and oxidized lactate directly. Therefore, DC-HMOP-LOX collabora-tively depleted lactate in the TME, which induced an immunocompetent TME by activating immune -promoting cells (dendritic cell, T cells, natural killer cells, and M1-macrophage), inactivating immuno-suppressive cells (M2-macrophage and bone marrow-derived suppressor cells), and regulating the levels of immune cytokines (IFN-c, TNF-a, IL-10, and IL-12). The immunocompetent TME ultimately strength-ened the antitumor effect of anti-PD1-based immunotherapy.(c) 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/)."

基金机构：Research Incubation Project of the Third Affiliated Hospital of Chongqing Medical University [KY08025]; Basic Research and Frontier Exploration Project of Yuz- hong District of Chongqing [20190107]; Chongqing Talent Plan [cstc2021ycjh-bgzxm0077]

基金资助正文："This study was supported by the Research Incubation Project of the Third Affiliated Hospital of Chongqing Medical University (KY08025) , Basic Research and Frontier Exploration Project of Yuz- hong District of Chongqing (20190107) , and Chongqing Talent Plan (cstc2021ycjh-bgzxm0077) ."