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 2021-11, Vol.278, p.121137-121137, Article 121137 |
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creator | Gunassekaran, Gowri Rangaswamy Poongkavithai Vadevoo, Sri Murugan Baek, Moon-Chang Lee, Byungheon |
description | 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. |
doi_str_mv | 10.1016/j.biomaterials.2021.121137 |
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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.</description><identifier>ISSN: 0142-9612</identifier><identifier>EISSN: 1878-5905</identifier><identifier>DOI: 10.1016/j.biomaterials.2021.121137</identifier><identifier>PMID: 34560422</identifier><language>eng</language><publisher>Netherlands: Elsevier Ltd</publisher><subject>Cellular Reprogramming ; Exosome ; Exosomes ; Humans ; Interleukin-4 receptor ; Interleukin-4 Receptor alpha Subunit ; M1 macrophage ; M2 macrophage ; Macrophages ; miR-511–3p ; Neoplasms - therapy ; NF-κB p50 ; Receptors, Interleukin-4 ; Tumor-associated macrophage ; Tumor-Associated Macrophages</subject><ispartof>Biomaterials, 2021-11, Vol.278, p.121137-121137, Article 121137</ispartof><rights>2021 Elsevier Ltd</rights><rights>Copyright © 2021 Elsevier Ltd. 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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.</description><subject>Cellular Reprogramming</subject><subject>Exosome</subject><subject>Exosomes</subject><subject>Humans</subject><subject>Interleukin-4 receptor</subject><subject>Interleukin-4 Receptor alpha Subunit</subject><subject>M1 macrophage</subject><subject>M2 macrophage</subject><subject>Macrophages</subject><subject>miR-511–3p</subject><subject>Neoplasms - therapy</subject><subject>NF-κB p50</subject><subject>Receptors, Interleukin-4</subject><subject>Tumor-associated macrophage</subject><subject>Tumor-Associated Macrophages</subject><issn>0142-9612</issn><issn>1878-5905</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNUU1v1DAQtRCILoW_gCxOXLLYjuMk3FD5qrQVl_ZsOfEk6yWOg-2lLb-LH8hUKWiPHCx79N7Me-NHyBvOtpxx9e6w7VzwJkN0ZkpbwQTfcsF5WT8hG97UTVG1rHpKNoxLUbSKizPyIqUDw5pJ8ZyclbJS-BIb8vuKU2_6GJa9GYHCXUjBQ6Iwj24GiGBpDnQICdUocpcwmeh-mezCTM2MqIkjZJr3QC93haQRelhyiNTNe9c5RI4eqzGG27yn3T0SlhjGaLx387iihUkp9A43sidmEo5A7SteTO47nAIvybMBN4dXj_c5ufn86fria7H79uXy4sOu6GVZ58IC46ZrOzxCKGtl29UDqNqa0naml4IPzAysbfqmlWXDVKOg4qyTLa9NpYbynLxd56LjH0dIWXuXepgmM0M4Ji2qWqlKqrJF6vuViiZTijDoJTpv4r3mTD-kpg_6NDX9kJpeU8Pm1486x86D_df6NyYkfFwJgNv-dBB16h3MPViH_521De5_dP4AoBO0GQ</recordid><startdate>202111</startdate><enddate>202111</enddate><creator>Gunassekaran, Gowri Rangaswamy</creator><creator>Poongkavithai Vadevoo, Sri Murugan</creator><creator>Baek, Moon-Chang</creator><creator>Lee, Byungheon</creator><general>Elsevier Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-4561-1027</orcidid></search><sort><creationdate>202111</creationdate><title>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</title><author>Gunassekaran, Gowri Rangaswamy ; Poongkavithai Vadevoo, Sri Murugan ; Baek, Moon-Chang ; Lee, Byungheon</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c437t-de01ab9bab9226dd49b7fe67da3dbac421f0af098c894380686e510b4917a56f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Cellular Reprogramming</topic><topic>Exosome</topic><topic>Exosomes</topic><topic>Humans</topic><topic>Interleukin-4 receptor</topic><topic>Interleukin-4 Receptor alpha Subunit</topic><topic>M1 macrophage</topic><topic>M2 macrophage</topic><topic>Macrophages</topic><topic>miR-511–3p</topic><topic>Neoplasms - therapy</topic><topic>NF-κB p50</topic><topic>Receptors, Interleukin-4</topic><topic>Tumor-associated macrophage</topic><topic>Tumor-Associated Macrophages</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gunassekaran, Gowri Rangaswamy</creatorcontrib><creatorcontrib>Poongkavithai Vadevoo, Sri Murugan</creatorcontrib><creatorcontrib>Baek, Moon-Chang</creatorcontrib><creatorcontrib>Lee, Byungheon</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Biomaterials</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gunassekaran, Gowri Rangaswamy</au><au>Poongkavithai Vadevoo, Sri Murugan</au><au>Baek, Moon-Chang</au><au>Lee, Byungheon</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>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</atitle><jtitle>Biomaterials</jtitle><addtitle>Biomaterials</addtitle><date>2021-11</date><risdate>2021</risdate><volume>278</volume><spage>121137</spage><epage>121137</epage><pages>121137-121137</pages><artnum>121137</artnum><issn>0142-9612</issn><eissn>1878-5905</eissn><abstract>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.</abstract><cop>Netherlands</cop><pub>Elsevier Ltd</pub><pmid>34560422</pmid><doi>10.1016/j.biomaterials.2021.121137</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0003-4561-1027</orcidid></addata></record> |
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subjects | Cellular Reprogramming Exosome Exosomes Humans Interleukin-4 receptor Interleukin-4 Receptor alpha Subunit M1 macrophage M2 macrophage Macrophages miR-511–3p Neoplasms - therapy NF-κB p50 Receptors, Interleukin-4 Tumor-associated macrophage Tumor-Associated Macrophages |
title | 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 |
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