PMID- 35093074 OWN - NLM STAT- MEDLINE DCOM- 20220331 LR - 20220401 IS - 1477-3155 (Electronic) IS - 1477-3155 (Linking) VI - 20 IP - 1 DP - 2022 Jan 29 TI - A nano-innate immune system activator for cancer therapy in a 4T1 tumor-bearing mouse model. PG - 54 LID - 10.1186/s12951-022-01265-4 [doi] LID - 54 AB - BACKGROUND: Harnessing the immune system to fight cancer has led to prominent clinical successes. Strategies to stimulate innate immune effectors are attracting considerable interest in cancer therapy. Here, through conjugating multivalent Fc fragments onto the surface of mesoporous silica nanoparticles (MSN), we developed a nanoparticle-based innate immune system activator (NISA) for breast cancer immunotherapy. METHODS: NISA was prepared through conjugating mouse IgG3 Fc to MSN surface. Then, long-chain PEG(5000), which was used to shield Fc to confer nanoparticle colloidal stability, was linked to the MSN surface via matrix metalloprotease-2 (MMP-2)-cleavable peptide (GPLGIAGQC). The activation of multiple components of innate immune system, including complement and the innate cells (macrophages and dendritic cells) and the associated anticancer effect were investigated. RESULTS: Fc fragments of NISA can be exposed through hydrolysis of long-chain PEG(5000) by highly expressed MMP-2 in tumor microenvironment. Then, effective stimulation and activation of multiple components of innate immune system, including complement, macrophages, and dendritic cells were obtained, leading to efficient antitumor effect in 4T1 breast cancer cells and orthotopic breast tumor model in mice. CONCLUSIONS: The antitumor potency conferred by NISA highlights the significance of stimulating multiple innate immune elements in cancer immunotherapy. CI - (c) 2022. The Author(s). FAU - Liu, Xiang-Yu AU - Liu XY AD - Hongqiao International Institute of Medicine, Tongren Hospital and State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China. FAU - Zhu, Mao-Hua AU - Zhu MH AD - Hongqiao International Institute of Medicine, Tongren Hospital and State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China. FAU - Wang, Xiao-Yu AU - Wang XY AD - Hongqiao International Institute of Medicine, Tongren Hospital and State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China. FAU - Dong, Xiao AU - Dong X AD - Hongqiao International Institute of Medicine, Tongren Hospital and State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China. FAU - Liu, Hai-Jun AU - Liu HJ AD - Hongqiao International Institute of Medicine, Tongren Hospital and State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China. FAU - Li, Rui-Yang AU - Li RY AD - Hongqiao International Institute of Medicine, Tongren Hospital and State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China. FAU - Jia, Shi-Chong AU - Jia SC AD - Hongqiao International Institute of Medicine, Tongren Hospital and State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China. FAU - Lu, Qin AU - Lu Q AD - Hongqiao International Institute of Medicine, Tongren Hospital and State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China. FAU - Zhao, Mei AU - Zhao M AD - Department of Pharmacy, Shanghai University of Medicine and Health Sciences, 279 Zhouzhu Road, Shanghai, 201318, China. FAU - Sun, Peng AU - Sun P AD - Department of General Surgery, Tongren Hospital, SJTU-SM, Shanghai, 200336, China. FAU - Chen, Hong-Zhuan AU - Chen HZ AD - Institute of Interdisciplinary Integrative Biomedical Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. FAU - Fang, Chao AU - Fang C AUID- ORCID: 0000-0002-9236-7752 AD - Hongqiao International Institute of Medicine, Tongren Hospital and State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China. fangchao32@sjtu.edu.cn. AD - Key Laboratory of Basic Pharmacology of Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, 563003, China. fangchao32@sjtu.edu.cn. LA - eng GR - 81602729/national natural science foundation of china/ GR - 81773274/national natural science foundation of china/ GR - 82073379/national natural science foundation of china/ GR - 16SG13/"shu guang" program of shanghai education development foundation and shanghai municipal education commission/ PT - Journal Article DEP - 20220129 PL - England TA - J Nanobiotechnology JT - Journal of nanobiotechnology JID - 101152208 SB - IM MH - Animals MH - Cell Line, Tumor MH - Immunotherapy MH - Macrophages MH - Mice MH - *Nanoparticles/therapeutic use MH - *Neoplasms MH - Tumor Microenvironment PMC - PMC8800325 OTO - NOTNLM OT - Breast cancer OT - Fc fragment OT - Immunotherapy OT - Innate immune system OT - Nanoparticles COIS- The authors have declared that no competing interest exists. EDAT- 2022/01/31 06:00 MHDA- 2022/04/01 06:00 PMCR- 2022/01/29 CRDT- 2022/01/30 20:26 PHST- 2021/07/18 00:00 [received] PHST- 2022/01/14 00:00 [accepted] PHST- 2022/01/30 20:26 [entrez] PHST- 2022/01/31 06:00 [pubmed] PHST- 2022/04/01 06:00 [medline] PHST- 2022/01/29 00:00 [pmc-release] AID - 10.1186/s12951-022-01265-4 [pii] AID - 1265 [pii] AID - 10.1186/s12951-022-01265-4 [doi] PST - epublish SO - J Nanobiotechnology. 2022 Jan 29;20(1):54. doi: 10.1186/s12951-022-01265-4.