Development of chimeric Nanobody-Granzyme B functionalized ferritin nanoparticles for precise tumor therapy
T-cell lymphomas (TCLs) are heterogeneous malignancies with limited treatment options and poor outcomes. The efficacy of traditional T-cell therapies, including chimeric antigen receptor (CAR) T cells, is often constrained by immunosuppressive factors and the tumor microenvironment. On the other han...
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Elsevier
2025-03-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825000532 |
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| author | Baijin Xia Huolun Feng Xinmiao Jiang Jialing Guo Keming Lin Wenxing Zhang Fan Xing Lixue Cao Yong Li Hui Zhang Xu Zhang Wenyu Li Fei Yu |
| author_facet | Baijin Xia Huolun Feng Xinmiao Jiang Jialing Guo Keming Lin Wenxing Zhang Fan Xing Lixue Cao Yong Li Hui Zhang Xu Zhang Wenyu Li Fei Yu |
| author_sort | Baijin Xia |
| collection | DOAJ |
| description | T-cell lymphomas (TCLs) are heterogeneous malignancies with limited treatment options and poor outcomes. The efficacy of traditional T-cell therapies, including chimeric antigen receptor (CAR) T cells, is often constrained by immunosuppressive factors and the tumor microenvironment. On the other hand, although direct Granzyme B (GrB) administration can effectively induce tumor cell apoptosis, it lacks universal tumor targeting and efficient cellular entry mechanisms. To address these limitations, we developed a novel nanoparticle-based therapy for the precise targeting of TCL tumor cells and the delivery of GrB. We fused nanobody (Nb) targeting CD30 and CD5 with GrB and coupled them to human ferritin (h-HFn) using the Gv/Sd system, creating a novel therapeutic nanoparticle named BiCD30/5-GF, which specifically targets CD30 and CD5 receptors on TCL tumor cells. The Nb-GrB conjugation enhances tumor targeting, while a Gv/Sd linker coupled to h-HFn further improves cellular transport and targeting. Additionally, the multimerization of GrB enhances its effectiveness. These nanoparticles demonstrated superior binding affinity and cytotoxicity in vitro compared to conventional treatments. In vivo studies on tumor-bearing mice showed significant tumor suppression and prolonged survival following treatment with BiCD30/5-GF nanoparticles. We also extended similar nanoparticle strategies for gastric cancer therapy, targeting FGFR4-expressing tumor cells. Our findings highlight the potential of engineered nanoparticles as effective and targeted therapeutic agents across various tumor types, offering promising prospects for clinical translation in cancer treatment. |
| format | Article |
| id | doaj-art-63a45bf070a343439b91f6b5b673648b |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-63a45bf070a343439b91f6b5b673648b2025-02-02T05:26:50ZengElsevierPharmacological Research1096-11862025-03-01213107628Development of chimeric Nanobody-Granzyme B functionalized ferritin nanoparticles for precise tumor therapyBaijin Xia0Huolun Feng1Xinmiao Jiang2Jialing Guo3Keming Lin4Wenxing Zhang5Fan Xing6Lixue Cao7Yong Li8Hui Zhang9Xu Zhang10Wenyu Li11Fei Yu12Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China; Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, ChinaDepartment of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; School of Medicine, South China University of Technology, Guangzhou 510006, ChinaLymphoma Department, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, ChinaMedical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, ChinaInstitute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, ChinaDepartment of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, ChinaMedical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, ChinaMedical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, ChinaDepartment of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, ChinaInstitute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Correspondence to: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, No. 74 Zhongshan Road 2, Yuexiu District, Guangzhou 510080, China.Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Correspondence to: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, No. 74 Zhongshan Road 2, Yuexiu District, Guangzhou 510080, China.Lymphoma Department, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; Correspondence to: Lymphoma Department, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China; Correspondence to: Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), No. 106 Zhongshan Road 2, Yuexiu District, Guangzhou 510080, China.T-cell lymphomas (TCLs) are heterogeneous malignancies with limited treatment options and poor outcomes. The efficacy of traditional T-cell therapies, including chimeric antigen receptor (CAR) T cells, is often constrained by immunosuppressive factors and the tumor microenvironment. On the other hand, although direct Granzyme B (GrB) administration can effectively induce tumor cell apoptosis, it lacks universal tumor targeting and efficient cellular entry mechanisms. To address these limitations, we developed a novel nanoparticle-based therapy for the precise targeting of TCL tumor cells and the delivery of GrB. We fused nanobody (Nb) targeting CD30 and CD5 with GrB and coupled them to human ferritin (h-HFn) using the Gv/Sd system, creating a novel therapeutic nanoparticle named BiCD30/5-GF, which specifically targets CD30 and CD5 receptors on TCL tumor cells. The Nb-GrB conjugation enhances tumor targeting, while a Gv/Sd linker coupled to h-HFn further improves cellular transport and targeting. Additionally, the multimerization of GrB enhances its effectiveness. These nanoparticles demonstrated superior binding affinity and cytotoxicity in vitro compared to conventional treatments. In vivo studies on tumor-bearing mice showed significant tumor suppression and prolonged survival following treatment with BiCD30/5-GF nanoparticles. We also extended similar nanoparticle strategies for gastric cancer therapy, targeting FGFR4-expressing tumor cells. Our findings highlight the potential of engineered nanoparticles as effective and targeted therapeutic agents across various tumor types, offering promising prospects for clinical translation in cancer treatment.http://www.sciencedirect.com/science/article/pii/S1043661825000532Granzyme BNanoparticleFerritinNanobodyTumor targeted therapy |
| spellingShingle | Baijin Xia Huolun Feng Xinmiao Jiang Jialing Guo Keming Lin Wenxing Zhang Fan Xing Lixue Cao Yong Li Hui Zhang Xu Zhang Wenyu Li Fei Yu Development of chimeric Nanobody-Granzyme B functionalized ferritin nanoparticles for precise tumor therapy Pharmacological Research Granzyme B Nanoparticle Ferritin Nanobody Tumor targeted therapy |
| title | Development of chimeric Nanobody-Granzyme B functionalized ferritin nanoparticles for precise tumor therapy |
| title_full | Development of chimeric Nanobody-Granzyme B functionalized ferritin nanoparticles for precise tumor therapy |
| title_fullStr | Development of chimeric Nanobody-Granzyme B functionalized ferritin nanoparticles for precise tumor therapy |
| title_full_unstemmed | Development of chimeric Nanobody-Granzyme B functionalized ferritin nanoparticles for precise tumor therapy |
| title_short | Development of chimeric Nanobody-Granzyme B functionalized ferritin nanoparticles for precise tumor therapy |
| title_sort | development of chimeric nanobody granzyme b functionalized ferritin nanoparticles for precise tumor therapy |
| topic | Granzyme B Nanoparticle Ferritin Nanobody Tumor targeted therapy |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825000532 |
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