Supramolecular polyrotaxane-based nano-theranostics enable cancer-cell stiffening for enhanced T-cell-mediated anticancer immunotherapy
Abstract Despite the tremendous therapeutic promise of activating stimulators of interferon genes (STING) enable to prime robust de novo T-cell responses, biomechanics-mediated immune inhibitory pathways hinder the cytotoxicity of T cells against tumor cells. Blocking cancer cell biomechanics-mediat...
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| Format: | Article |
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57718-5 |
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| author | Haifen Luo Jingqi Lv Peiye Wen Shan Zhang Wen Ma Zhen Yang |
| author_facet | Haifen Luo Jingqi Lv Peiye Wen Shan Zhang Wen Ma Zhen Yang |
| author_sort | Haifen Luo |
| collection | DOAJ |
| description | Abstract Despite the tremendous therapeutic promise of activating stimulators of interferon genes (STING) enable to prime robust de novo T-cell responses, biomechanics-mediated immune inhibitory pathways hinder the cytotoxicity of T cells against tumor cells. Blocking cancer cell biomechanics-mediated evasion provides a feasible strategy for augmenting STING activation-mediated anti-tumor therapeutic efficacy. Here, we fabricate a redox-responsive Methyl-β-cyclodextrin (MeβCD)-based supramolecular polyrotaxanes (MSPs), where the amphiphilic diselenide-bridged axle polymer loads MeβCD by the host-guest interaction and end-caping with two near-infrared (NIR) fluorescence probes IR783. The MSPs self-assemble with STING agonists diABZIs into nanoparticles (RDPNs@diABZIs), which enable simultaneous release of MeβCD and diABZIs in the redox tumor microenvironment. After the released diABZIs activate STING on antigen-presenting cells (APCs), de novo T-cell responses are initiated. Meanwhile, the released MeβCD depletes membrane cholesterol to overcome cancer-cell mechanical softness, which enhances the CTL-mediated killing of cancer cells. In the female tumor-bearing mouse model, we demonstrate that RDPNs@diABZIs lead to effective tumor regression and generate long-term immunological memory. Furthermore, RDPNs@diABZIs can achieve significant tumor eradication, with these mice remaining survival for at least 2 months. |
| format | Article |
| id | doaj-art-b48efe920dba4b4b980f8f728432a771 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b48efe920dba4b4b980f8f728432a7712025-08-20T02:59:57ZengNature PortfolioNature Communications2041-17232025-03-0116111310.1038/s41467-025-57718-5Supramolecular polyrotaxane-based nano-theranostics enable cancer-cell stiffening for enhanced T-cell-mediated anticancer immunotherapyHaifen Luo0Jingqi Lv1Peiye Wen2Shan Zhang3Wen Ma4Zhen Yang5Strait Laboratory of Flexible Electronics (SLoFE), Fujian Key Laboratory of Flexible Electronics, Key Laboratory of Opto-Electronic Science and Technology for Medicine of Ministry of Education, College of Photonic and Electronic Engineering, Strait Institute of Flexible Electronics (SIFE, Future Technologies), Fujian Normal UniversityStrait Laboratory of Flexible Electronics (SLoFE), Fujian Key Laboratory of Flexible Electronics, Key Laboratory of Opto-Electronic Science and Technology for Medicine of Ministry of Education, College of Photonic and Electronic Engineering, Strait Institute of Flexible Electronics (SIFE, Future Technologies), Fujian Normal UniversityStrait Laboratory of Flexible Electronics (SLoFE), Fujian Key Laboratory of Flexible Electronics, Key Laboratory of Opto-Electronic Science and Technology for Medicine of Ministry of Education, College of Photonic and Electronic Engineering, Strait Institute of Flexible Electronics (SIFE, Future Technologies), Fujian Normal UniversityStrait Laboratory of Flexible Electronics (SLoFE), Fujian Key Laboratory of Flexible Electronics, Key Laboratory of Opto-Electronic Science and Technology for Medicine of Ministry of Education, College of Photonic and Electronic Engineering, Strait Institute of Flexible Electronics (SIFE, Future Technologies), Fujian Normal UniversityStrait Laboratory of Flexible Electronics (SLoFE), Fujian Key Laboratory of Flexible Electronics, Key Laboratory of Opto-Electronic Science and Technology for Medicine of Ministry of Education, College of Photonic and Electronic Engineering, Strait Institute of Flexible Electronics (SIFE, Future Technologies), Fujian Normal UniversityStrait Laboratory of Flexible Electronics (SLoFE), Fujian Key Laboratory of Flexible Electronics, Key Laboratory of Opto-Electronic Science and Technology for Medicine of Ministry of Education, College of Photonic and Electronic Engineering, Strait Institute of Flexible Electronics (SIFE, Future Technologies), Fujian Normal UniversityAbstract Despite the tremendous therapeutic promise of activating stimulators of interferon genes (STING) enable to prime robust de novo T-cell responses, biomechanics-mediated immune inhibitory pathways hinder the cytotoxicity of T cells against tumor cells. Blocking cancer cell biomechanics-mediated evasion provides a feasible strategy for augmenting STING activation-mediated anti-tumor therapeutic efficacy. Here, we fabricate a redox-responsive Methyl-β-cyclodextrin (MeβCD)-based supramolecular polyrotaxanes (MSPs), where the amphiphilic diselenide-bridged axle polymer loads MeβCD by the host-guest interaction and end-caping with two near-infrared (NIR) fluorescence probes IR783. The MSPs self-assemble with STING agonists diABZIs into nanoparticles (RDPNs@diABZIs), which enable simultaneous release of MeβCD and diABZIs in the redox tumor microenvironment. After the released diABZIs activate STING on antigen-presenting cells (APCs), de novo T-cell responses are initiated. Meanwhile, the released MeβCD depletes membrane cholesterol to overcome cancer-cell mechanical softness, which enhances the CTL-mediated killing of cancer cells. In the female tumor-bearing mouse model, we demonstrate that RDPNs@diABZIs lead to effective tumor regression and generate long-term immunological memory. Furthermore, RDPNs@diABZIs can achieve significant tumor eradication, with these mice remaining survival for at least 2 months.https://doi.org/10.1038/s41467-025-57718-5 |
| spellingShingle | Haifen Luo Jingqi Lv Peiye Wen Shan Zhang Wen Ma Zhen Yang Supramolecular polyrotaxane-based nano-theranostics enable cancer-cell stiffening for enhanced T-cell-mediated anticancer immunotherapy Nature Communications |
| title | Supramolecular polyrotaxane-based nano-theranostics enable cancer-cell stiffening for enhanced T-cell-mediated anticancer immunotherapy |
| title_full | Supramolecular polyrotaxane-based nano-theranostics enable cancer-cell stiffening for enhanced T-cell-mediated anticancer immunotherapy |
| title_fullStr | Supramolecular polyrotaxane-based nano-theranostics enable cancer-cell stiffening for enhanced T-cell-mediated anticancer immunotherapy |
| title_full_unstemmed | Supramolecular polyrotaxane-based nano-theranostics enable cancer-cell stiffening for enhanced T-cell-mediated anticancer immunotherapy |
| title_short | Supramolecular polyrotaxane-based nano-theranostics enable cancer-cell stiffening for enhanced T-cell-mediated anticancer immunotherapy |
| title_sort | supramolecular polyrotaxane based nano theranostics enable cancer cell stiffening for enhanced t cell mediated anticancer immunotherapy |
| url | https://doi.org/10.1038/s41467-025-57718-5 |
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