Nanoparticles (NPs)-mediated Siglec15 silencing and macrophage repolarization for enhanced cancer immunotherapy.
10.1016/j.apsb.2023.07.012
- Author:
Xiaodi LIU
1
;
Qi ZHANG
2
;
Yixia LIANG
3
;
Shiyu XIONG
2
;
Yan CAI
4
;
Jincheng CAO
2
;
Yanni XU
2
;
Xiaolin XU
2
;
Ye WU
2
;
Qiang LU
1
;
Xiaoding XU
2
;
Baoming LUO
2
Author Information
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.
- Publication Type:Journal Article
- Keywords:
Cancer immunotherapy;
Hepatocellular carcinoma;
Macrophage repolarization;
Nanoparticles;
Siglec15;
T cell infiltration;
T cell proliferation;
Tumor-associated macrophages
- From:
Acta Pharmaceutica Sinica B
2023;13(12):5048-5059
- CountryChina
- Language:English
-
Abstract:
T 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 (IFNγ) 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 reduction-responsive nanoparticles (NPs) made with poly (disulfide amide) (PDSA) and lipid-poly (ethylene glycol) (lipid-PEG) for systemic delivery of Siglec15 siRNA (siSiglec15) and IFNγ 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 IFNγ and siSiglec15 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.
