Allosteric targeted drug delivery for enhanced blood-brain barrier penetration via mimicking transmembrane domain interactions
Abstract Current strategies for active targeting in the brain are entirely based on the effective interaction of the ligand with the orthosteric sites of specific receptors on the blood-brain barrier (BBB), which is highly susceptible to various pathophysiological factors and limits the efficacy of...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58746-x |
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| author | Kaicheng Tang Zhongjie Tang Miaomiao Niu Zuyin Kuang Weiwei Xue Xinyu Wang Xinlong Liu Yang Yu Seongdong Jeong Yifan Ma Annette Wu Betty Y. S. Kim Wen Jiang Zhaogang Yang Chong Li |
| author_facet | Kaicheng Tang Zhongjie Tang Miaomiao Niu Zuyin Kuang Weiwei Xue Xinyu Wang Xinlong Liu Yang Yu Seongdong Jeong Yifan Ma Annette Wu Betty Y. S. Kim Wen Jiang Zhaogang Yang Chong Li |
| author_sort | Kaicheng Tang |
| collection | DOAJ |
| description | Abstract Current strategies for active targeting in the brain are entirely based on the effective interaction of the ligand with the orthosteric sites of specific receptors on the blood-brain barrier (BBB), which is highly susceptible to various pathophysiological factors and limits the efficacy of drug delivery. Here, we propose an allosteric targeted drug delivery strategy that targets classical BBB transmembrane receptors by designing peptide ligands that specifically bind to their transmembrane domains. This strategy prevents competitive interference from endogenous ligands and antibodies by using the insulin receptor and integrin αv as model targets, respectively, and can effectively overcome pseudotargets or target loss caused by shedding or mutating the extracellular domain of target receptors. Moreover, these ligands can be spontaneously embedded in the phospholipid layer of lipid carriers using a plug-and-play approach without chemical modification, with excellent tunability and immunocompatibility. Overall, this allosteric targeted drug delivery strategy can be applied to multiple receptor targets and drug carriers and offers promising therapeutic benefits in brain diseases. |
| format | Article |
| id | doaj-art-63772cc6b2f242f7aa83bf84f8a37055 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-63772cc6b2f242f7aa83bf84f8a370552025-08-20T02:12:02ZengNature PortfolioNature Communications2041-17232025-04-0116111810.1038/s41467-025-58746-xAllosteric targeted drug delivery for enhanced blood-brain barrier penetration via mimicking transmembrane domain interactionsKaicheng Tang0Zhongjie Tang1Miaomiao Niu2Zuyin Kuang3Weiwei Xue4Xinyu Wang5Xinlong Liu6Yang Yu7Seongdong Jeong8Yifan Ma9Annette Wu10Betty Y. S. Kim11Wen Jiang12Zhaogang Yang13Chong Li14Medical Research Institute, College of Pharmaceutical Sciences, Southwest UniversityMedical Research Institute, College of Pharmaceutical Sciences, Southwest UniversitySchool of Basic Medicine and Clinical Pharmacy, China Pharmaceutical UniversityMedical Research Institute, College of Pharmaceutical Sciences, Southwest UniversitySchool of Pharmaceutical Sciences, Chongqing UniversityMedical Research Institute, College of Pharmaceutical Sciences, Southwest UniversityMedical Research Institute, College of Pharmaceutical Sciences, Southwest UniversityMedical Research Institute, College of Pharmaceutical Sciences, Southwest UniversityDepartment of Neurosurgery, The University of Texas MD Anderson Cancer CenterDepartment of Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Neurosurgery, The University of Texas MD Anderson Cancer CenterDepartment of Radiation Oncology, The University of Texas MD Anderson Cancer CenterSchool of Life Sciences, Jilin UniversityMedical Research Institute, College of Pharmaceutical Sciences, Southwest UniversityAbstract Current strategies for active targeting in the brain are entirely based on the effective interaction of the ligand with the orthosteric sites of specific receptors on the blood-brain barrier (BBB), which is highly susceptible to various pathophysiological factors and limits the efficacy of drug delivery. Here, we propose an allosteric targeted drug delivery strategy that targets classical BBB transmembrane receptors by designing peptide ligands that specifically bind to their transmembrane domains. This strategy prevents competitive interference from endogenous ligands and antibodies by using the insulin receptor and integrin αv as model targets, respectively, and can effectively overcome pseudotargets or target loss caused by shedding or mutating the extracellular domain of target receptors. Moreover, these ligands can be spontaneously embedded in the phospholipid layer of lipid carriers using a plug-and-play approach without chemical modification, with excellent tunability and immunocompatibility. Overall, this allosteric targeted drug delivery strategy can be applied to multiple receptor targets and drug carriers and offers promising therapeutic benefits in brain diseases.https://doi.org/10.1038/s41467-025-58746-x |
| spellingShingle | Kaicheng Tang Zhongjie Tang Miaomiao Niu Zuyin Kuang Weiwei Xue Xinyu Wang Xinlong Liu Yang Yu Seongdong Jeong Yifan Ma Annette Wu Betty Y. S. Kim Wen Jiang Zhaogang Yang Chong Li Allosteric targeted drug delivery for enhanced blood-brain barrier penetration via mimicking transmembrane domain interactions Nature Communications |
| title | Allosteric targeted drug delivery for enhanced blood-brain barrier penetration via mimicking transmembrane domain interactions |
| title_full | Allosteric targeted drug delivery for enhanced blood-brain barrier penetration via mimicking transmembrane domain interactions |
| title_fullStr | Allosteric targeted drug delivery for enhanced blood-brain barrier penetration via mimicking transmembrane domain interactions |
| title_full_unstemmed | Allosteric targeted drug delivery for enhanced blood-brain barrier penetration via mimicking transmembrane domain interactions |
| title_short | Allosteric targeted drug delivery for enhanced blood-brain barrier penetration via mimicking transmembrane domain interactions |
| title_sort | allosteric targeted drug delivery for enhanced blood brain barrier penetration via mimicking transmembrane domain interactions |
| url | https://doi.org/10.1038/s41467-025-58746-x |
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