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.

中文翻译：

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设计用于极化巨噬细胞以抑制肿瘤生长的无载体 CXCR4 靶向纳米复合物。

介绍

癌症转移（癌症死亡的主要原因）的治疗选择是有限的。趋化因子受体 CXCR4 是一种有吸引力的癌症治疗靶点，因为它通过诱导癌细胞和巨噬细胞迁移来介导转移。在这里，我们设计了靶向 CXCR4 的无载体 RNA 蛋白纳米复合物，不仅抑制细胞迁移，而且将巨噬细胞极化为 M1 表型。

材料和方法

将 CXCR4 靶向单链可变片段 (scFv) 抗体融合到 3030 Da RNA 结合鱼精蛋白肽 (RSQSSRRYYRQRQRSRRRRRRS)。自组装纳米复合物是通过将 CXCR4-scFv-鱼精蛋白融合蛋白 (CXCR4-scFv-RBM) 与 miR-127-5p 混合形成的，miR-127-5p 是一种显示介导 M1 巨噬细胞极化的 miRNA。RNA-蛋白质纳米复合物的特征在于其物理化学性质和治疗功效。

结果

CXCR4 靶向 RNA 蛋白纳米复合物同时充当靶向配体、巨噬细胞极化药物和 miRNA 递送载体。我们的无载体 RNA 蛋白纳米复合物与 CXCR4 阳性巨噬细胞和乳腺癌细胞特异性结合，显示出高载药量（~ 90% w/w），并且无毒。此外，这些 RNA 蛋白纳米复合物显着抑制癌症和免疫细胞迁移（75% 至 99%），将巨噬细胞强烈极化为抑制肿瘤的 M1 表型，并抑制三阴性乳腺癌小鼠模型中的肿瘤生长

结论

我们设计了一类新型的无毒 RNA 蛋白纳米复合物，可调节肿瘤基质。这些纳米复合物是临床批准的化疗药物的有希望的候选药物。