M1 macrophage exosomes engineered to foster M1 polarization and target the IL-4 receptor inhibit tumor growth by reprogramming tumor-associated macrophages into M1-like macrophages

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 inhib...

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Veröffentlicht in:Biomaterials Jg. 278; S. 121137
Hauptverfasser: Gunassekaran, Gowri Rangaswamy, Poongkavithai Vadevoo, Sri Murugan, Baek, Moon-Chang, Lee, Byungheon
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Netherlands Elsevier Ltd 01.11.2021
Schlagworte:
biocompatible materials
Cellular Reprogramming
Exosome
Exosomes
fluorescence
Humans
immunity
immunotherapy
interleukin-4
Interleukin-4 receptor
Interleukin-4 Receptor alpha Subunit
liver
M1 macrophage
M2 macrophage
Macrophages
miR-511–3p
neoplasms
Neoplasms - therapy
NF-κB p50
Receptors, Interleukin-4
Tumor-associated macrophage
Tumor-Associated Macrophages
M2 macrophage
miR-511–3p
Exosome
M1 macrophage
Interleukin-4 receptor
Tumor-associated macrophage
NF-κB p50
ISSN:0142-9612, 1878-5905, 1878-5905
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0142-9612
1878-5905
1878-5905
DOI:10.1016/j.biomaterials.2021.121137