Co-encapsulation of norcantharidin prodrugs and lomitapide in nanoparticles to regulate CCL4 expression by inhibiting Wnt/β-catenin pathway for improved anti-tumor immunotherapy
Abstract In the absence of tumor antigen specificity, direct chemokine administration carries the risk of significant “on-target, off-tumor” toxicities, highlighting the need for small-molecule approaches with reduced immunogenicity. This study investigates the synergistic potential of norcantharidi...
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2025-05-01
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| Series: | Journal of Nanobiotechnology |
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| Online Access: | https://doi.org/10.1186/s12951-025-03425-8 |
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| author | Feng Zhao Liming Gong Ping Wang Dong Chen Shijie Cao Feifei Yang Manqing Tang Yuanyuan Meng Yuming Wang Lin Miao Yunfei Li Wei Huang |
| author_facet | Feng Zhao Liming Gong Ping Wang Dong Chen Shijie Cao Feifei Yang Manqing Tang Yuanyuan Meng Yuming Wang Lin Miao Yunfei Li Wei Huang |
| author_sort | Feng Zhao |
| collection | DOAJ |
| description | Abstract In the absence of tumor antigen specificity, direct chemokine administration carries the risk of significant “on-target, off-tumor” toxicities, highlighting the need for small-molecule approaches with reduced immunogenicity. This study investigates the synergistic potential of norcantharidin (NCTD) and lomitapide (lomi) in selectively restoring CCL4 expression by deactivating the tumor intrinsic β-catenin pathway. Due to its similar lipophilicity to lomi and potential to suppress β-catenin, NCTD prodrug (C12) was selected to be co-encapsulated with lomi in a nanoparticle-mediated co-delivery system (NP“C12 + lomi”). The NP“C12 + lomi” formulation exhibited a high encapsulation rate, uniform particle size, and suitability for therapeutic use. It effectively inhibited the proliferation of 4T1 cells and restored CCL4 expression. In both primary breast tumor and surgically resected tumor mouse models, NP“C12 + lomi” significantly increased the proportion of CD8+ cells in primary tumors, blood, and lung metastases, approximately doubling their presence. This led to a prolongation of median survival in mice to 59 days. Furthermore, when combined with an immune checkpoint inhibitor, NP“C12 + lomi” substantially inhibited tumor growth and lung metastasis without affecting body weight or causing major tissue or organ damage. This was attributed to the controlled dissociation of the nanoparticle and the subsequent modulation of C12 and lomi, which mitigated CCL4-related toxicity. This study provides valuable insights into the safe production of chemokines using a small-molecule pair through a nanosystem and presents a robust chemo-immunological cascade therapy strategy, demonstrating significant efficacy against malignant metastatic tumors. Graphical abstract |
| format | Article |
| id | doaj-art-ebb58e62f0ec4b278462f9cc52db606f |
| institution | Kabale University |
| issn | 1477-3155 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj-art-ebb58e62f0ec4b278462f9cc52db606f2025-08-20T03:48:18ZengBMCJournal of Nanobiotechnology1477-31552025-05-0123112610.1186/s12951-025-03425-8Co-encapsulation of norcantharidin prodrugs and lomitapide in nanoparticles to regulate CCL4 expression by inhibiting Wnt/β-catenin pathway for improved anti-tumor immunotherapyFeng Zhao0Liming Gong1Ping Wang2Dong Chen3Shijie Cao4Feifei Yang5Manqing Tang6Yuanyuan Meng7Yuming Wang8Lin Miao9Yunfei Li10Wei Huang11College of Chinese Materia Medica, Tianjin University of Traditional Chinese MedicineState Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical CollegeCollege of Chinese Materia Medica, Tianjin University of Traditional Chinese MedicineSuzhou Kintor Pharmaceuticals, Inc.State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese MedicineKey Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicines, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical CollegeCollege of Chinese Materia Medica, Tianjin University of Traditional Chinese MedicineCollege of Chinese Materia Medica, Tianjin University of Traditional Chinese MedicineCollege of Chinese Materia Medica, Tianjin University of Traditional Chinese MedicineState Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese MedicineCollege of Chinese Materia Medica, Tianjin University of Traditional Chinese MedicineState Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical CollegeAbstract In the absence of tumor antigen specificity, direct chemokine administration carries the risk of significant “on-target, off-tumor” toxicities, highlighting the need for small-molecule approaches with reduced immunogenicity. This study investigates the synergistic potential of norcantharidin (NCTD) and lomitapide (lomi) in selectively restoring CCL4 expression by deactivating the tumor intrinsic β-catenin pathway. Due to its similar lipophilicity to lomi and potential to suppress β-catenin, NCTD prodrug (C12) was selected to be co-encapsulated with lomi in a nanoparticle-mediated co-delivery system (NP“C12 + lomi”). The NP“C12 + lomi” formulation exhibited a high encapsulation rate, uniform particle size, and suitability for therapeutic use. It effectively inhibited the proliferation of 4T1 cells and restored CCL4 expression. In both primary breast tumor and surgically resected tumor mouse models, NP“C12 + lomi” significantly increased the proportion of CD8+ cells in primary tumors, blood, and lung metastases, approximately doubling their presence. This led to a prolongation of median survival in mice to 59 days. Furthermore, when combined with an immune checkpoint inhibitor, NP“C12 + lomi” substantially inhibited tumor growth and lung metastasis without affecting body weight or causing major tissue or organ damage. This was attributed to the controlled dissociation of the nanoparticle and the subsequent modulation of C12 and lomi, which mitigated CCL4-related toxicity. This study provides valuable insights into the safe production of chemokines using a small-molecule pair through a nanosystem and presents a robust chemo-immunological cascade therapy strategy, demonstrating significant efficacy against malignant metastatic tumors. Graphical abstracthttps://doi.org/10.1186/s12951-025-03425-8Chemokine immunotherapySmall molecule strategyβ-catenin inhibitionNanoparticle colocalizationMetastasis mitigation |
| spellingShingle | Feng Zhao Liming Gong Ping Wang Dong Chen Shijie Cao Feifei Yang Manqing Tang Yuanyuan Meng Yuming Wang Lin Miao Yunfei Li Wei Huang Co-encapsulation of norcantharidin prodrugs and lomitapide in nanoparticles to regulate CCL4 expression by inhibiting Wnt/β-catenin pathway for improved anti-tumor immunotherapy Journal of Nanobiotechnology Chemokine immunotherapy Small molecule strategy β-catenin inhibition Nanoparticle colocalization Metastasis mitigation |
| title | Co-encapsulation of norcantharidin prodrugs and lomitapide in nanoparticles to regulate CCL4 expression by inhibiting Wnt/β-catenin pathway for improved anti-tumor immunotherapy |
| title_full | Co-encapsulation of norcantharidin prodrugs and lomitapide in nanoparticles to regulate CCL4 expression by inhibiting Wnt/β-catenin pathway for improved anti-tumor immunotherapy |
| title_fullStr | Co-encapsulation of norcantharidin prodrugs and lomitapide in nanoparticles to regulate CCL4 expression by inhibiting Wnt/β-catenin pathway for improved anti-tumor immunotherapy |
| title_full_unstemmed | Co-encapsulation of norcantharidin prodrugs and lomitapide in nanoparticles to regulate CCL4 expression by inhibiting Wnt/β-catenin pathway for improved anti-tumor immunotherapy |
| title_short | Co-encapsulation of norcantharidin prodrugs and lomitapide in nanoparticles to regulate CCL4 expression by inhibiting Wnt/β-catenin pathway for improved anti-tumor immunotherapy |
| title_sort | co encapsulation of norcantharidin prodrugs and lomitapide in nanoparticles to regulate ccl4 expression by inhibiting wnt β catenin pathway for improved anti tumor immunotherapy |
| topic | Chemokine immunotherapy Small molecule strategy β-catenin inhibition Nanoparticle colocalization Metastasis mitigation |
| url | https://doi.org/10.1186/s12951-025-03425-8 |
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