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Carrier-Free CXCR4-Targeted Nanoplexes Designed for Polarizing Macrophages to Suppress Tumor Growth.
Cellular and Molecular Bioengineering ( IF 2.477 ) Pub Date : 2019-11-14 , DOI: 10.1007/s12195-019-00589-w
Michael B Deci,Maixian Liu,Jacqueline Gonya,Christine J Lee,Tingyi Li,Scott W Ferguson,Emily E Bonacquisti,Jinli Wang,Juliane Nguyen

Introduction Treatment options for cancer metastases, the primary cause of cancer mortality, are limited. The chemokine receptor CXCR4 is an attractive therapeutic target in cancer because it mediates metastasis by inducing cancer cell and macrophage migration. Here we engineered carrier-free CXCR4-targeting RNA-protein nanoplexes that not only inhibited cellular migration but also polarized macrophages to the M1 phenotype. Materials and Methods A CXCR4-targeting single-chain variable fragment (scFv) antibody was fused to a 3030 Da RNA-binding protamine peptide (RSQSRSRYYRQRQRSRRRRRRS). Self-assembling nanoplexes were formed by mixing the CXCR4-scFv-protamine fusion protein (CXCR4-scFv-RBM) with miR-127-5p, a miRNA shown to mediate M1 macrophage polarization. RNA-protein nanoplexes were characterized with regard to their physicochemical properties and therapeutic efficacy. Results CXCR4-targeting RNA-protein nanoplexes simultaneously acted as a targeting ligand, a macrophage polarizing drug, and a miRNA delivery vehicle. Our carrier-free, RNA-protein nanoplexes specifically bound to CXCR4-positive macrophages and breast cancer cells, showed high drug loading (~ 90% w/w), and are non-toxic. Further, these RNA-protein nanoplexes significantly inhibited cancer and immune cell migration (75 to 99%), robustly polarized macrophages to the tumor-suppressive M1 phenotype, and inhibited tumor growth in a mouse model of triple-negative breast cancer. Conclusions We engineered a novel class of non-toxic RNA-protein nanoplexes that modulate the tumor stroma. These nanoplexes are promising candidates for add-ons to clinically approved chemotherapeutics.
更新日期:2019-11-01

 

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