PD-L1 siRNA hitched polyethyleneimine-elastase constituting nanovesicle induces tumor immunogenicity and PD-L1 silencing for synergistic antitumor immunotherapy
Background PD-1/PD-L1 blockade has become a powerful method to treat malignant tumors. However, a large proportion of patients still do not benefit from this treatment, due to low tumor immunogenicity and low tumor penetration of the agents. Recently, neutrophil elastase has been shown to induce rob...
Ausführliche Beschreibung
Autor*in: |
Du, Li [verfasserIn] Gong, Yao [verfasserIn] Zhang, Xiaoying [verfasserIn] Sun, Jide [verfasserIn] Gao, Fengxia [verfasserIn] Shen, Meiying [verfasserIn] Bai, Huili [verfasserIn] Yang, Tiantian [verfasserIn] Cheng, Xiaoxue [verfasserIn] Li, Siqiao [verfasserIn] Peng, Jian [verfasserIn] Liu, Zhangling [verfasserIn] Ding, Shijia [verfasserIn] Chen, Junman [verfasserIn] Cheng, Wei [verfasserIn] |
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E-Artikel |
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Sprache: |
Englisch |
Erschienen: |
2024 |
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Schlagwörter: |
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Anmerkung: |
© The Author(s) 2024 |
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Übergeordnetes Werk: |
Enthalten in: Journal of nanobiotechnology - BioMed Central, 2003, 22(2024), 1 vom: 27. Juli |
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Übergeordnetes Werk: |
volume:22 ; year:2024 ; number:1 ; day:27 ; month:07 |
Links: |
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DOI / URN: |
10.1186/s12951-024-02700-4 |
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Katalog-ID: |
SPR056756054 |
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520 | |a Background PD-1/PD-L1 blockade has become a powerful method to treat malignant tumors. However, a large proportion of patients still do not benefit from this treatment, due to low tumor immunogenicity and low tumor penetration of the agents. Recently, neutrophil elastase has been shown to induce robust tumor immunogenicity, while the insufficient enzyme activity at the tumor site restricted its anti-tumor application. Here, we designed polyethyleneimine-modified neutrophil elastase (PEI-elastase) loaded with PD-L1small interfering RNA (PD-L1 siRNA) for improving enzymatic activity and delivering siRNA to tumor, which was expected to solve the above-mentioned problems. Results We first demonstrated that PEI-elastase possessed high enzymatic activity, which was also identified as an excellent gene-delivery material. Then, we synthesized anti-tumor lipopolymer (P-E/S Lip) by encapsulating PEI-elastase and PD-L1siRNA with pH-responsive anionic liposomes. The P-E/S Lip could be rapidly cleaved in tumor acidic environment, leading to exposure of the PEI-elastase/PD-L1 siRNA. Consequently, PEI-elastase induced powerful tumor immunogenicity upon direct tumor killing with minimal toxicity to normal cells. In parallel, PEI-elastase delivered PD-L1siRNA into the tumor and reduced PD-L1 expression. Orthotopic tumor administration of P-E/S Lip not only attenuated primary tumor growth, but also produced systemic anti-tumor immune response to inhibit growth of distant tumors and metastasis. Moreover, intravenous administration of P-E/S Lip into mice bearing subcutaneous tumors leaded to an effective inhibition of established B16-F10 tumor and 4T1 tumor, with histological analyses indicating an absence of detectable toxicity. Conclusions In our study, a protease-based nanoplatform was used to cooperatively provoke robust tumor immunogenicity and down-regulate PD-L1 expression, which exhibited great potential as a combination therapy for precisely treating solid tumors. Graphical Abstract | ||
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650 | 4 | |a Polyethyleneimine |7 (dpeaa)DE-He213 | |
650 | 4 | |a PD-L1 siRNA |7 (dpeaa)DE-He213 | |
650 | 4 | |a Liposomes |7 (dpeaa)DE-He213 | |
650 | 4 | |a Anti-tumor immune response |7 (dpeaa)DE-He213 | |
700 | 1 | |a Gong, Yao |e verfasserin |4 aut | |
700 | 1 | |a Zhang, Xiaoying |e verfasserin |4 aut | |
700 | 1 | |a Sun, Jide |e verfasserin |4 aut | |
700 | 1 | |a Gao, Fengxia |e verfasserin |4 aut | |
700 | 1 | |a Shen, Meiying |e verfasserin |4 aut | |
700 | 1 | |a Bai, Huili |e verfasserin |4 aut | |
700 | 1 | |a Yang, Tiantian |e verfasserin |4 aut | |
700 | 1 | |a Cheng, Xiaoxue |e verfasserin |4 aut | |
700 | 1 | |a Li, Siqiao |e verfasserin |4 aut | |
700 | 1 | |a Peng, Jian |e verfasserin |4 aut | |
700 | 1 | |a Liu, Zhangling |e verfasserin |4 aut | |
700 | 1 | |a Ding, Shijia |e verfasserin |4 aut | |
700 | 1 | |a Chen, Junman |e verfasserin |4 aut | |
700 | 1 | |a Cheng, Wei |e verfasserin |4 aut | |
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10.1186/s12951-024-02700-4 doi (DE-627)SPR056756054 (SPR)s12951-024-02700-4-e DE-627 ger DE-627 rakwb eng 540 610 VZ 58.30 bkl 50.94 bkl Du, Li verfasserin aut PD-L1 siRNA hitched polyethyleneimine-elastase constituting nanovesicle induces tumor immunogenicity and PD-L1 silencing for synergistic antitumor immunotherapy 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Background PD-1/PD-L1 blockade has become a powerful method to treat malignant tumors. However, a large proportion of patients still do not benefit from this treatment, due to low tumor immunogenicity and low tumor penetration of the agents. Recently, neutrophil elastase has been shown to induce robust tumor immunogenicity, while the insufficient enzyme activity at the tumor site restricted its anti-tumor application. Here, we designed polyethyleneimine-modified neutrophil elastase (PEI-elastase) loaded with PD-L1small interfering RNA (PD-L1 siRNA) for improving enzymatic activity and delivering siRNA to tumor, which was expected to solve the above-mentioned problems. Results We first demonstrated that PEI-elastase possessed high enzymatic activity, which was also identified as an excellent gene-delivery material. Then, we synthesized anti-tumor lipopolymer (P-E/S Lip) by encapsulating PEI-elastase and PD-L1siRNA with pH-responsive anionic liposomes. The P-E/S Lip could be rapidly cleaved in tumor acidic environment, leading to exposure of the PEI-elastase/PD-L1 siRNA. Consequently, PEI-elastase induced powerful tumor immunogenicity upon direct tumor killing with minimal toxicity to normal cells. In parallel, PEI-elastase delivered PD-L1siRNA into the tumor and reduced PD-L1 expression. Orthotopic tumor administration of P-E/S Lip not only attenuated primary tumor growth, but also produced systemic anti-tumor immune response to inhibit growth of distant tumors and metastasis. Moreover, intravenous administration of P-E/S Lip into mice bearing subcutaneous tumors leaded to an effective inhibition of established B16-F10 tumor and 4T1 tumor, with histological analyses indicating an absence of detectable toxicity. Conclusions In our study, a protease-based nanoplatform was used to cooperatively provoke robust tumor immunogenicity and down-regulate PD-L1 expression, which exhibited great potential as a combination therapy for precisely treating solid tumors. Graphical Abstract Elastase (dpeaa)DE-He213 Polyethyleneimine (dpeaa)DE-He213 PD-L1 siRNA (dpeaa)DE-He213 Liposomes (dpeaa)DE-He213 Anti-tumor immune response (dpeaa)DE-He213 Gong, Yao verfasserin aut Zhang, Xiaoying verfasserin aut Sun, Jide verfasserin aut Gao, Fengxia verfasserin aut Shen, Meiying verfasserin aut Bai, Huili verfasserin aut Yang, Tiantian verfasserin aut Cheng, Xiaoxue verfasserin aut Li, Siqiao verfasserin aut Peng, Jian verfasserin aut Liu, Zhangling verfasserin aut Ding, Shijia verfasserin aut Chen, Junman verfasserin aut Cheng, Wei verfasserin aut Enthalten in Journal of nanobiotechnology BioMed Central, 2003 22(2024), 1 vom: 27. Juli (DE-627)362770328 (DE-600)2100022-0 1477-3155 nnns volume:22 year:2024 number:1 day:27 month:07 https://dx.doi.org/10.1186/s12951-024-02700-4 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2027 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2108 GBV_ILN_2111 GBV_ILN_2119 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 58.30 VZ 50.94 VZ AR 22 2024 1 27 07 |
spelling |
10.1186/s12951-024-02700-4 doi (DE-627)SPR056756054 (SPR)s12951-024-02700-4-e DE-627 ger DE-627 rakwb eng 540 610 VZ 58.30 bkl 50.94 bkl Du, Li verfasserin aut PD-L1 siRNA hitched polyethyleneimine-elastase constituting nanovesicle induces tumor immunogenicity and PD-L1 silencing for synergistic antitumor immunotherapy 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Background PD-1/PD-L1 blockade has become a powerful method to treat malignant tumors. However, a large proportion of patients still do not benefit from this treatment, due to low tumor immunogenicity and low tumor penetration of the agents. Recently, neutrophil elastase has been shown to induce robust tumor immunogenicity, while the insufficient enzyme activity at the tumor site restricted its anti-tumor application. Here, we designed polyethyleneimine-modified neutrophil elastase (PEI-elastase) loaded with PD-L1small interfering RNA (PD-L1 siRNA) for improving enzymatic activity and delivering siRNA to tumor, which was expected to solve the above-mentioned problems. Results We first demonstrated that PEI-elastase possessed high enzymatic activity, which was also identified as an excellent gene-delivery material. Then, we synthesized anti-tumor lipopolymer (P-E/S Lip) by encapsulating PEI-elastase and PD-L1siRNA with pH-responsive anionic liposomes. The P-E/S Lip could be rapidly cleaved in tumor acidic environment, leading to exposure of the PEI-elastase/PD-L1 siRNA. Consequently, PEI-elastase induced powerful tumor immunogenicity upon direct tumor killing with minimal toxicity to normal cells. In parallel, PEI-elastase delivered PD-L1siRNA into the tumor and reduced PD-L1 expression. Orthotopic tumor administration of P-E/S Lip not only attenuated primary tumor growth, but also produced systemic anti-tumor immune response to inhibit growth of distant tumors and metastasis. Moreover, intravenous administration of P-E/S Lip into mice bearing subcutaneous tumors leaded to an effective inhibition of established B16-F10 tumor and 4T1 tumor, with histological analyses indicating an absence of detectable toxicity. Conclusions In our study, a protease-based nanoplatform was used to cooperatively provoke robust tumor immunogenicity and down-regulate PD-L1 expression, which exhibited great potential as a combination therapy for precisely treating solid tumors. Graphical Abstract Elastase (dpeaa)DE-He213 Polyethyleneimine (dpeaa)DE-He213 PD-L1 siRNA (dpeaa)DE-He213 Liposomes (dpeaa)DE-He213 Anti-tumor immune response (dpeaa)DE-He213 Gong, Yao verfasserin aut Zhang, Xiaoying verfasserin aut Sun, Jide verfasserin aut Gao, Fengxia verfasserin aut Shen, Meiying verfasserin aut Bai, Huili verfasserin aut Yang, Tiantian verfasserin aut Cheng, Xiaoxue verfasserin aut Li, Siqiao verfasserin aut Peng, Jian verfasserin aut Liu, Zhangling verfasserin aut Ding, Shijia verfasserin aut Chen, Junman verfasserin aut Cheng, Wei verfasserin aut Enthalten in Journal of nanobiotechnology BioMed Central, 2003 22(2024), 1 vom: 27. Juli (DE-627)362770328 (DE-600)2100022-0 1477-3155 nnns volume:22 year:2024 number:1 day:27 month:07 https://dx.doi.org/10.1186/s12951-024-02700-4 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2027 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2108 GBV_ILN_2111 GBV_ILN_2119 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 58.30 VZ 50.94 VZ AR 22 2024 1 27 07 |
allfields_unstemmed |
10.1186/s12951-024-02700-4 doi (DE-627)SPR056756054 (SPR)s12951-024-02700-4-e DE-627 ger DE-627 rakwb eng 540 610 VZ 58.30 bkl 50.94 bkl Du, Li verfasserin aut PD-L1 siRNA hitched polyethyleneimine-elastase constituting nanovesicle induces tumor immunogenicity and PD-L1 silencing for synergistic antitumor immunotherapy 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Background PD-1/PD-L1 blockade has become a powerful method to treat malignant tumors. However, a large proportion of patients still do not benefit from this treatment, due to low tumor immunogenicity and low tumor penetration of the agents. Recently, neutrophil elastase has been shown to induce robust tumor immunogenicity, while the insufficient enzyme activity at the tumor site restricted its anti-tumor application. Here, we designed polyethyleneimine-modified neutrophil elastase (PEI-elastase) loaded with PD-L1small interfering RNA (PD-L1 siRNA) for improving enzymatic activity and delivering siRNA to tumor, which was expected to solve the above-mentioned problems. Results We first demonstrated that PEI-elastase possessed high enzymatic activity, which was also identified as an excellent gene-delivery material. Then, we synthesized anti-tumor lipopolymer (P-E/S Lip) by encapsulating PEI-elastase and PD-L1siRNA with pH-responsive anionic liposomes. The P-E/S Lip could be rapidly cleaved in tumor acidic environment, leading to exposure of the PEI-elastase/PD-L1 siRNA. Consequently, PEI-elastase induced powerful tumor immunogenicity upon direct tumor killing with minimal toxicity to normal cells. In parallel, PEI-elastase delivered PD-L1siRNA into the tumor and reduced PD-L1 expression. Orthotopic tumor administration of P-E/S Lip not only attenuated primary tumor growth, but also produced systemic anti-tumor immune response to inhibit growth of distant tumors and metastasis. Moreover, intravenous administration of P-E/S Lip into mice bearing subcutaneous tumors leaded to an effective inhibition of established B16-F10 tumor and 4T1 tumor, with histological analyses indicating an absence of detectable toxicity. Conclusions In our study, a protease-based nanoplatform was used to cooperatively provoke robust tumor immunogenicity and down-regulate PD-L1 expression, which exhibited great potential as a combination therapy for precisely treating solid tumors. Graphical Abstract Elastase (dpeaa)DE-He213 Polyethyleneimine (dpeaa)DE-He213 PD-L1 siRNA (dpeaa)DE-He213 Liposomes (dpeaa)DE-He213 Anti-tumor immune response (dpeaa)DE-He213 Gong, Yao verfasserin aut Zhang, Xiaoying verfasserin aut Sun, Jide verfasserin aut Gao, Fengxia verfasserin aut Shen, Meiying verfasserin aut Bai, Huili verfasserin aut Yang, Tiantian verfasserin aut Cheng, Xiaoxue verfasserin aut Li, Siqiao verfasserin aut Peng, Jian verfasserin aut Liu, Zhangling verfasserin aut Ding, Shijia verfasserin aut Chen, Junman verfasserin aut Cheng, Wei verfasserin aut Enthalten in Journal of nanobiotechnology BioMed Central, 2003 22(2024), 1 vom: 27. Juli (DE-627)362770328 (DE-600)2100022-0 1477-3155 nnns volume:22 year:2024 number:1 day:27 month:07 https://dx.doi.org/10.1186/s12951-024-02700-4 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2027 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2108 GBV_ILN_2111 GBV_ILN_2119 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 58.30 VZ 50.94 VZ AR 22 2024 1 27 07 |
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10.1186/s12951-024-02700-4 doi (DE-627)SPR056756054 (SPR)s12951-024-02700-4-e DE-627 ger DE-627 rakwb eng 540 610 VZ 58.30 bkl 50.94 bkl Du, Li verfasserin aut PD-L1 siRNA hitched polyethyleneimine-elastase constituting nanovesicle induces tumor immunogenicity and PD-L1 silencing for synergistic antitumor immunotherapy 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Background PD-1/PD-L1 blockade has become a powerful method to treat malignant tumors. However, a large proportion of patients still do not benefit from this treatment, due to low tumor immunogenicity and low tumor penetration of the agents. Recently, neutrophil elastase has been shown to induce robust tumor immunogenicity, while the insufficient enzyme activity at the tumor site restricted its anti-tumor application. Here, we designed polyethyleneimine-modified neutrophil elastase (PEI-elastase) loaded with PD-L1small interfering RNA (PD-L1 siRNA) for improving enzymatic activity and delivering siRNA to tumor, which was expected to solve the above-mentioned problems. Results We first demonstrated that PEI-elastase possessed high enzymatic activity, which was also identified as an excellent gene-delivery material. Then, we synthesized anti-tumor lipopolymer (P-E/S Lip) by encapsulating PEI-elastase and PD-L1siRNA with pH-responsive anionic liposomes. The P-E/S Lip could be rapidly cleaved in tumor acidic environment, leading to exposure of the PEI-elastase/PD-L1 siRNA. Consequently, PEI-elastase induced powerful tumor immunogenicity upon direct tumor killing with minimal toxicity to normal cells. In parallel, PEI-elastase delivered PD-L1siRNA into the tumor and reduced PD-L1 expression. Orthotopic tumor administration of P-E/S Lip not only attenuated primary tumor growth, but also produced systemic anti-tumor immune response to inhibit growth of distant tumors and metastasis. Moreover, intravenous administration of P-E/S Lip into mice bearing subcutaneous tumors leaded to an effective inhibition of established B16-F10 tumor and 4T1 tumor, with histological analyses indicating an absence of detectable toxicity. Conclusions In our study, a protease-based nanoplatform was used to cooperatively provoke robust tumor immunogenicity and down-regulate PD-L1 expression, which exhibited great potential as a combination therapy for precisely treating solid tumors. Graphical Abstract Elastase (dpeaa)DE-He213 Polyethyleneimine (dpeaa)DE-He213 PD-L1 siRNA (dpeaa)DE-He213 Liposomes (dpeaa)DE-He213 Anti-tumor immune response (dpeaa)DE-He213 Gong, Yao verfasserin aut Zhang, Xiaoying verfasserin aut Sun, Jide verfasserin aut Gao, Fengxia verfasserin aut Shen, Meiying verfasserin aut Bai, Huili verfasserin aut Yang, Tiantian verfasserin aut Cheng, Xiaoxue verfasserin aut Li, Siqiao verfasserin aut Peng, Jian verfasserin aut Liu, Zhangling verfasserin aut Ding, Shijia verfasserin aut Chen, Junman verfasserin aut Cheng, Wei verfasserin aut Enthalten in Journal of nanobiotechnology BioMed Central, 2003 22(2024), 1 vom: 27. Juli (DE-627)362770328 (DE-600)2100022-0 1477-3155 nnns volume:22 year:2024 number:1 day:27 month:07 https://dx.doi.org/10.1186/s12951-024-02700-4 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2027 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2108 GBV_ILN_2111 GBV_ILN_2119 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 58.30 VZ 50.94 VZ AR 22 2024 1 27 07 |
allfieldsSound |
10.1186/s12951-024-02700-4 doi (DE-627)SPR056756054 (SPR)s12951-024-02700-4-e DE-627 ger DE-627 rakwb eng 540 610 VZ 58.30 bkl 50.94 bkl Du, Li verfasserin aut PD-L1 siRNA hitched polyethyleneimine-elastase constituting nanovesicle induces tumor immunogenicity and PD-L1 silencing for synergistic antitumor immunotherapy 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Background PD-1/PD-L1 blockade has become a powerful method to treat malignant tumors. However, a large proportion of patients still do not benefit from this treatment, due to low tumor immunogenicity and low tumor penetration of the agents. Recently, neutrophil elastase has been shown to induce robust tumor immunogenicity, while the insufficient enzyme activity at the tumor site restricted its anti-tumor application. Here, we designed polyethyleneimine-modified neutrophil elastase (PEI-elastase) loaded with PD-L1small interfering RNA (PD-L1 siRNA) for improving enzymatic activity and delivering siRNA to tumor, which was expected to solve the above-mentioned problems. Results We first demonstrated that PEI-elastase possessed high enzymatic activity, which was also identified as an excellent gene-delivery material. Then, we synthesized anti-tumor lipopolymer (P-E/S Lip) by encapsulating PEI-elastase and PD-L1siRNA with pH-responsive anionic liposomes. The P-E/S Lip could be rapidly cleaved in tumor acidic environment, leading to exposure of the PEI-elastase/PD-L1 siRNA. Consequently, PEI-elastase induced powerful tumor immunogenicity upon direct tumor killing with minimal toxicity to normal cells. In parallel, PEI-elastase delivered PD-L1siRNA into the tumor and reduced PD-L1 expression. Orthotopic tumor administration of P-E/S Lip not only attenuated primary tumor growth, but also produced systemic anti-tumor immune response to inhibit growth of distant tumors and metastasis. Moreover, intravenous administration of P-E/S Lip into mice bearing subcutaneous tumors leaded to an effective inhibition of established B16-F10 tumor and 4T1 tumor, with histological analyses indicating an absence of detectable toxicity. Conclusions In our study, a protease-based nanoplatform was used to cooperatively provoke robust tumor immunogenicity and down-regulate PD-L1 expression, which exhibited great potential as a combination therapy for precisely treating solid tumors. Graphical Abstract Elastase (dpeaa)DE-He213 Polyethyleneimine (dpeaa)DE-He213 PD-L1 siRNA (dpeaa)DE-He213 Liposomes (dpeaa)DE-He213 Anti-tumor immune response (dpeaa)DE-He213 Gong, Yao verfasserin aut Zhang, Xiaoying verfasserin aut Sun, Jide verfasserin aut Gao, Fengxia verfasserin aut Shen, Meiying verfasserin aut Bai, Huili verfasserin aut Yang, Tiantian verfasserin aut Cheng, Xiaoxue verfasserin aut Li, Siqiao verfasserin aut Peng, Jian verfasserin aut Liu, Zhangling verfasserin aut Ding, Shijia verfasserin aut Chen, Junman verfasserin aut Cheng, Wei verfasserin aut Enthalten in Journal of nanobiotechnology BioMed Central, 2003 22(2024), 1 vom: 27. Juli (DE-627)362770328 (DE-600)2100022-0 1477-3155 nnns volume:22 year:2024 number:1 day:27 month:07 https://dx.doi.org/10.1186/s12951-024-02700-4 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2027 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2108 GBV_ILN_2111 GBV_ILN_2119 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 58.30 VZ 50.94 VZ AR 22 2024 1 27 07 |
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Enthalten in Journal of nanobiotechnology 22(2024), 1 vom: 27. Juli volume:22 year:2024 number:1 day:27 month:07 |
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Du, Li @@aut@@ Gong, Yao @@aut@@ Zhang, Xiaoying @@aut@@ Sun, Jide @@aut@@ Gao, Fengxia @@aut@@ Shen, Meiying @@aut@@ Bai, Huili @@aut@@ Yang, Tiantian @@aut@@ Cheng, Xiaoxue @@aut@@ Li, Siqiao @@aut@@ Peng, Jian @@aut@@ Liu, Zhangling @@aut@@ Ding, Shijia @@aut@@ Chen, Junman @@aut@@ Cheng, Wei @@aut@@ |
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However, a large proportion of patients still do not benefit from this treatment, due to low tumor immunogenicity and low tumor penetration of the agents. Recently, neutrophil elastase has been shown to induce robust tumor immunogenicity, while the insufficient enzyme activity at the tumor site restricted its anti-tumor application. Here, we designed polyethyleneimine-modified neutrophil elastase (PEI-elastase) loaded with PD-L1small interfering RNA (PD-L1 siRNA) for improving enzymatic activity and delivering siRNA to tumor, which was expected to solve the above-mentioned problems. Results We first demonstrated that PEI-elastase possessed high enzymatic activity, which was also identified as an excellent gene-delivery material. Then, we synthesized anti-tumor lipopolymer (P-E/S Lip) by encapsulating PEI-elastase and PD-L1siRNA with pH-responsive anionic liposomes. The P-E/S Lip could be rapidly cleaved in tumor acidic environment, leading to exposure of the PEI-elastase/PD-L1 siRNA. 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Du, Li ddc 540 bkl 58.30 bkl 50.94 misc Elastase misc Polyethyleneimine misc PD-L1 siRNA misc Liposomes misc Anti-tumor immune response PD-L1 siRNA hitched polyethyleneimine-elastase constituting nanovesicle induces tumor immunogenicity and PD-L1 silencing for synergistic antitumor immunotherapy |
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540 610 VZ 58.30 bkl 50.94 bkl PD-L1 siRNA hitched polyethyleneimine-elastase constituting nanovesicle induces tumor immunogenicity and PD-L1 silencing for synergistic antitumor immunotherapy Elastase (dpeaa)DE-He213 Polyethyleneimine (dpeaa)DE-He213 PD-L1 siRNA (dpeaa)DE-He213 Liposomes (dpeaa)DE-He213 Anti-tumor immune response (dpeaa)DE-He213 |
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Du, Li Gong, Yao Zhang, Xiaoying Sun, Jide Gao, Fengxia Shen, Meiying Bai, Huili Yang, Tiantian Cheng, Xiaoxue Li, Siqiao Peng, Jian Liu, Zhangling Ding, Shijia Chen, Junman Cheng, Wei |
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pd-l1 sirna hitched polyethyleneimine-elastase constituting nanovesicle induces tumor immunogenicity and pd-l1 silencing for synergistic antitumor immunotherapy |
title_auth |
PD-L1 siRNA hitched polyethyleneimine-elastase constituting nanovesicle induces tumor immunogenicity and PD-L1 silencing for synergistic antitumor immunotherapy |
abstract |
Background PD-1/PD-L1 blockade has become a powerful method to treat malignant tumors. However, a large proportion of patients still do not benefit from this treatment, due to low tumor immunogenicity and low tumor penetration of the agents. Recently, neutrophil elastase has been shown to induce robust tumor immunogenicity, while the insufficient enzyme activity at the tumor site restricted its anti-tumor application. Here, we designed polyethyleneimine-modified neutrophil elastase (PEI-elastase) loaded with PD-L1small interfering RNA (PD-L1 siRNA) for improving enzymatic activity and delivering siRNA to tumor, which was expected to solve the above-mentioned problems. Results We first demonstrated that PEI-elastase possessed high enzymatic activity, which was also identified as an excellent gene-delivery material. Then, we synthesized anti-tumor lipopolymer (P-E/S Lip) by encapsulating PEI-elastase and PD-L1siRNA with pH-responsive anionic liposomes. The P-E/S Lip could be rapidly cleaved in tumor acidic environment, leading to exposure of the PEI-elastase/PD-L1 siRNA. Consequently, PEI-elastase induced powerful tumor immunogenicity upon direct tumor killing with minimal toxicity to normal cells. In parallel, PEI-elastase delivered PD-L1siRNA into the tumor and reduced PD-L1 expression. Orthotopic tumor administration of P-E/S Lip not only attenuated primary tumor growth, but also produced systemic anti-tumor immune response to inhibit growth of distant tumors and metastasis. Moreover, intravenous administration of P-E/S Lip into mice bearing subcutaneous tumors leaded to an effective inhibition of established B16-F10 tumor and 4T1 tumor, with histological analyses indicating an absence of detectable toxicity. Conclusions In our study, a protease-based nanoplatform was used to cooperatively provoke robust tumor immunogenicity and down-regulate PD-L1 expression, which exhibited great potential as a combination therapy for precisely treating solid tumors. Graphical Abstract © The Author(s) 2024 |
abstractGer |
Background PD-1/PD-L1 blockade has become a powerful method to treat malignant tumors. However, a large proportion of patients still do not benefit from this treatment, due to low tumor immunogenicity and low tumor penetration of the agents. Recently, neutrophil elastase has been shown to induce robust tumor immunogenicity, while the insufficient enzyme activity at the tumor site restricted its anti-tumor application. Here, we designed polyethyleneimine-modified neutrophil elastase (PEI-elastase) loaded with PD-L1small interfering RNA (PD-L1 siRNA) for improving enzymatic activity and delivering siRNA to tumor, which was expected to solve the above-mentioned problems. Results We first demonstrated that PEI-elastase possessed high enzymatic activity, which was also identified as an excellent gene-delivery material. Then, we synthesized anti-tumor lipopolymer (P-E/S Lip) by encapsulating PEI-elastase and PD-L1siRNA with pH-responsive anionic liposomes. The P-E/S Lip could be rapidly cleaved in tumor acidic environment, leading to exposure of the PEI-elastase/PD-L1 siRNA. Consequently, PEI-elastase induced powerful tumor immunogenicity upon direct tumor killing with minimal toxicity to normal cells. In parallel, PEI-elastase delivered PD-L1siRNA into the tumor and reduced PD-L1 expression. Orthotopic tumor administration of P-E/S Lip not only attenuated primary tumor growth, but also produced systemic anti-tumor immune response to inhibit growth of distant tumors and metastasis. Moreover, intravenous administration of P-E/S Lip into mice bearing subcutaneous tumors leaded to an effective inhibition of established B16-F10 tumor and 4T1 tumor, with histological analyses indicating an absence of detectable toxicity. Conclusions In our study, a protease-based nanoplatform was used to cooperatively provoke robust tumor immunogenicity and down-regulate PD-L1 expression, which exhibited great potential as a combination therapy for precisely treating solid tumors. Graphical Abstract © The Author(s) 2024 |
abstract_unstemmed |
Background PD-1/PD-L1 blockade has become a powerful method to treat malignant tumors. However, a large proportion of patients still do not benefit from this treatment, due to low tumor immunogenicity and low tumor penetration of the agents. Recently, neutrophil elastase has been shown to induce robust tumor immunogenicity, while the insufficient enzyme activity at the tumor site restricted its anti-tumor application. Here, we designed polyethyleneimine-modified neutrophil elastase (PEI-elastase) loaded with PD-L1small interfering RNA (PD-L1 siRNA) for improving enzymatic activity and delivering siRNA to tumor, which was expected to solve the above-mentioned problems. Results We first demonstrated that PEI-elastase possessed high enzymatic activity, which was also identified as an excellent gene-delivery material. Then, we synthesized anti-tumor lipopolymer (P-E/S Lip) by encapsulating PEI-elastase and PD-L1siRNA with pH-responsive anionic liposomes. The P-E/S Lip could be rapidly cleaved in tumor acidic environment, leading to exposure of the PEI-elastase/PD-L1 siRNA. Consequently, PEI-elastase induced powerful tumor immunogenicity upon direct tumor killing with minimal toxicity to normal cells. In parallel, PEI-elastase delivered PD-L1siRNA into the tumor and reduced PD-L1 expression. Orthotopic tumor administration of P-E/S Lip not only attenuated primary tumor growth, but also produced systemic anti-tumor immune response to inhibit growth of distant tumors and metastasis. Moreover, intravenous administration of P-E/S Lip into mice bearing subcutaneous tumors leaded to an effective inhibition of established B16-F10 tumor and 4T1 tumor, with histological analyses indicating an absence of detectable toxicity. Conclusions In our study, a protease-based nanoplatform was used to cooperatively provoke robust tumor immunogenicity and down-regulate PD-L1 expression, which exhibited great potential as a combination therapy for precisely treating solid tumors. Graphical Abstract © The Author(s) 2024 |
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PD-L1 siRNA hitched polyethyleneimine-elastase constituting nanovesicle induces tumor immunogenicity and PD-L1 silencing for synergistic antitumor immunotherapy |
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https://dx.doi.org/10.1186/s12951-024-02700-4 |
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Gong, Yao Zhang, Xiaoying Sun, Jide Gao, Fengxia Shen, Meiying Bai, Huili Yang, Tiantian Cheng, Xiaoxue Li, Siqiao Peng, Jian Liu, Zhangling Ding, Shijia Chen, Junman Cheng, Wei |
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Consequently, PEI-elastase induced powerful tumor immunogenicity upon direct tumor killing with minimal toxicity to normal cells. In parallel, PEI-elastase delivered PD-L1siRNA into the tumor and reduced PD-L1 expression. Orthotopic tumor administration of P-E/S Lip not only attenuated primary tumor growth, but also produced systemic anti-tumor immune response to inhibit growth of distant tumors and metastasis. Moreover, intravenous administration of P-E/S Lip into mice bearing subcutaneous tumors leaded to an effective inhibition of established B16-F10 tumor and 4T1 tumor, with histological analyses indicating an absence of detectable toxicity. Conclusions In our study, a protease-based nanoplatform was used to cooperatively provoke robust tumor immunogenicity and down-regulate PD-L1 expression, which exhibited great potential as a combination therapy for precisely treating solid tumors. 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