Nanoparticles (NPs)-mediated Siglec15 silencing and macrophage repolarization for enhanced cancer immunotherapy  

作　　者：Xiaodi Liu Qi Zhang Yixia Liang Shiyu Xiong Yan Cai Jincheng Cao Yanni Xu Xiaolin Xu Ye Wu Qiang Lu Xiaoding Xu Baoming Luo 

机构地区：[1]Department of Ultrasound,Laboratory of Ultrasound Imaging and Drug,West China Hospital,Sichuan University,Chengdu 610041,China [2]Department of Ultrasound,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510120,China [3]Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510120,China [4]Department of Ultrasound,Central People's Hospital of Zhanjiang,Zhanjiang 524045,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第12期5048-5059,共12页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82171944,81873899,China);the Natural Science Foundation of Guangdong Province(2021A1515012611,China);the National Natural Science Foundation of China(82171952,81801719,China);Postdoctoral Research and Development Fund Project of West China Hospital(2023HXBH063,China).

摘　　要：cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer immunotherapy.Emerging evidence has shown that interferon-gamma(IFN)could enhance CXCL9 secretion from macrophages to recruit T cells,but Siglec15 expressed on TAMs can attenuate T cell proliferation.Therefore,targeted regulation of macrophage function could be a promising strategy to enhance cancer immunotherapy via concurrently promoting the infiltration and proliferation of T cells in tumor tissues.We herein developed reductionresponsive nanoparticles(NPs)made with poly(disulfide amide)(PDSA)and lipid-poly(ethylene glycol)(lipid-PEG)for systemic delivery of Siglec15 siRNA(siSiglec15)and IFN for enhanced cancer immunotherapy.After intravenous administration,these cargo-loaded could highly accumulate in the tumor tissues and be efficiently internalized by tumor-associated macrophages(TAMs).With the highly concentrated glutathione(GSH)in the cytoplasm to destroy the nanostructure,the loaded IFN and si-Siglec15 could be rapidly released,which could respectively repolarize macrophage phenotype to enhance CXCL9 secretion for T cell infiltration and silence Siglec15 expression to promote T cell proliferation,leading to significant inhibition of hepatocellular carcinoma(HCC)growth when combining with the immune checkpoint inhibitor.The strategy developed herein could be used as an effective tool to enhance cancer immunotherapy.

关 键 词：NANOPARTICLES Tumor-associated macrophages Macrophage repolarization T cell infiltration T cell proliferation Cancer immunotherapy Siglec15 Hepatocellular carcinoma 

分 类 号：R73[医药卫生—肿瘤]