M2-polarized, pro-tumoral tumor-associated macrophages (TAMs) express the interleukin-4 receptor (IL4R) at higher levels compared with M1-polarized, anti-tumoral macrophages. In this study, we harnessed M1 macrophage-derived exosomes engineered to foster M1 polarization and target IL4R for the inhibition of tumor growth by reprogramming TAMs into M1-like macrophages. M1 exosomes were transfected with NF-κB p50 siRNA and miR-511–3p to enhance M1 polarization and were surface-modified with IL4RPep-1, an IL4R-binding peptide, to target the IL4 receptor of TAMs (named IL4R-Exo(si/mi). IL4R-Exo(si/mi) were internalized and downregulated target gens in M2 macrophages and decreased M2 markers, while increasing M1 markers, more efficiently compared with untargeted and control peptide-labeled exosomes and exosomes from non-immune, normal cells. Whole-body fluorescence imaging showed that IL4R-Exo(si/mi) homed to tumors at higher levels compared with the liver, unlike untargeted and control peptide-labeled exosomes. Systemic administration of IL4R-Exo(si/mi) inhibited tumor growth, downregulated target genes, and decreased the levels of M2 cytokines and immune-suppressive cells, while increasing the levels of M1 cytokines and immune-stimulatory cells, more efficiently than untargeted and control peptide-labeled exosomes. These results suggest that IL4R-Exo(si/mi) inhibits tumor growth by reprogramming TAMs into M1-like macrophages and increasing anti-tumor immunity, thus representing a novel cancer immunotherapy.

与 M1 极化的抗肿瘤巨噬细胞相比，M2 极化的促肿瘤肿瘤相关巨噬细胞 (TAM) 以更高水平表达白细胞介素 4 受体 (IL4R)。在这项研究中，我们利用 M1 巨噬细胞衍生的外泌体，通过将 TAM 重编程为 M1 样巨噬细胞来促进 M1 极化和靶向 IL4R 以抑制肿瘤生长。用 NF-κB p50 siRNA 和 miR-511-3p 转染 M1 外泌体以增强 M1 极化，并用 IL4RPep-1（一种 IL4R 结合肽）进行表面修饰，以靶向 TAM 的 IL4 受体（命名为 IL4R-Exo（si /mi). IL4R-Exo(si/mi) 在 M2 巨噬细胞中被内化和下调靶基因并减少 M2 标志物，同时增加 M1 标志物，与非靶向和对照肽标记的外泌体和来自非免疫、正常的外泌体相比更有效细胞。全身荧光成像显示，与非靶向和对照肽标记的外泌体不同，与肝脏相比，IL4R-Exo(si/mi) 以更高的水平归巢于肿瘤。全身给药 IL4R-Exo(si/mi) 抑制肿瘤生长，下调靶基因，降低 M2 细胞因子和免疫抑制细胞的水平，同时增加 M1 细胞因子和免疫刺激细胞的水平，比非靶向和非靶向给药更有效。控制肽标记的外泌体。这些结果表明，IL4R-Exo(si/mi) 通过将 TAM 重编程为 M1 样巨噬细胞并增加抗肿瘤免疫力来抑制肿瘤生长，因此代表了一种新的 全身给药 IL4R-Exo(si/mi) 抑制肿瘤生长，下调靶基因，降低 M2 细胞因子和免疫抑制细胞的水平，同时增加 M1 细胞因子和免疫刺激细胞的水平，比非靶向和非靶向给药更有效。控制肽标记的外泌体。这些结果表明，IL4R-Exo(si/mi) 通过将 TAM 重编程为 M1 样巨噬细胞并增加抗肿瘤免疫力来抑制肿瘤生长，因此代表了一种新的 全身给药 IL4R-Exo(si/mi) 抑制肿瘤生长，下调靶基因，降低 M2 细胞因子和免疫抑制细胞的水平，同时增加 M1 细胞因子和免疫刺激细胞的水平，比非靶向和非靶向给药更有效。控制肽标记的外泌体。这些结果表明，IL4R-Exo(si/mi) 通过将 TAM 重编程为 M1 样巨噬细胞并增加抗肿瘤免疫力来抑制肿瘤生长，因此代表了一种新的癌症免疫治疗。