Microenvironment-confined kinetic elucidation and implementation of a DNA nano-phage with a shielded internal computing layer
Abstract Multiple receptor analysis-based DNA molecular computation has been developed to mitigate the off-target effect caused by nonspecific expression of cell membrane receptors. However, it is quite difficult to involve nanobodies into molecular computation with programmed recognition order beca...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56219-9 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832585607389380608 |
|---|---|
| author | Decui Tang Shuoyao He Yani Yang Yuqi Zeng Mengyi Xiong Ding Ding Weijun Wei Yifan Lyu Xiao-Bing Zhang Weihong Tan |
| author_facet | Decui Tang Shuoyao He Yani Yang Yuqi Zeng Mengyi Xiong Ding Ding Weijun Wei Yifan Lyu Xiao-Bing Zhang Weihong Tan |
| author_sort | Decui Tang |
| collection | DOAJ |
| description | Abstract Multiple receptor analysis-based DNA molecular computation has been developed to mitigate the off-target effect caused by nonspecific expression of cell membrane receptors. However, it is quite difficult to involve nanobodies into molecular computation with programmed recognition order because of the “always-on” response mode and the inconvenient molecular programming. Here we propose a spatial segregation-based molecular computing strategy with a shielded internal computing layer termed DNA nano-phage (DNP) to program nanobody into DNA molecular computation and build a series of kinetic models to elucidate the mechanism of microenvironment-confinement. We explain the contradiction between fast molecular diffusion and effective DNA computation using a “diffusion trap” theory and comprehensively overcome the kinetic bottleneck of DNP by determining the rate-limiting step. We predict and verify that identifying trace amount of target cells in complex cell mixtures is an intrinsic merit of microenvironment-confined DNA computation. Finally, we show that DNP can efficiently work in complex human blood samples by shielding the interference of erythrocytes and enhance phagocytosis of macrophages toward target cells by blocking CD47-SIRPα pathway. |
| format | Article |
| id | doaj-art-f4b9d33d42c6472c8e6643cd5dcd748a |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-f4b9d33d42c6472c8e6643cd5dcd748a2025-01-26T12:41:38ZengNature PortfolioNature Communications2041-17232025-01-0116111310.1038/s41467-025-56219-9Microenvironment-confined kinetic elucidation and implementation of a DNA nano-phage with a shielded internal computing layerDecui Tang0Shuoyao He1Yani Yang2Yuqi Zeng3Mengyi Xiong4Ding Ding5Weijun Wei6Yifan Lyu7Xiao-Bing Zhang8Weihong Tan9Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan UniversityMolecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan UniversityMolecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan UniversityMolecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan UniversityMolecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan UniversityInstitute of Molecular Medicine (IMM), Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityDepartment of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityMolecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan UniversityMolecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan UniversityInstitute of Molecular Medicine (IMM), Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityAbstract Multiple receptor analysis-based DNA molecular computation has been developed to mitigate the off-target effect caused by nonspecific expression of cell membrane receptors. However, it is quite difficult to involve nanobodies into molecular computation with programmed recognition order because of the “always-on” response mode and the inconvenient molecular programming. Here we propose a spatial segregation-based molecular computing strategy with a shielded internal computing layer termed DNA nano-phage (DNP) to program nanobody into DNA molecular computation and build a series of kinetic models to elucidate the mechanism of microenvironment-confinement. We explain the contradiction between fast molecular diffusion and effective DNA computation using a “diffusion trap” theory and comprehensively overcome the kinetic bottleneck of DNP by determining the rate-limiting step. We predict and verify that identifying trace amount of target cells in complex cell mixtures is an intrinsic merit of microenvironment-confined DNA computation. Finally, we show that DNP can efficiently work in complex human blood samples by shielding the interference of erythrocytes and enhance phagocytosis of macrophages toward target cells by blocking CD47-SIRPα pathway.https://doi.org/10.1038/s41467-025-56219-9 |
| spellingShingle | Decui Tang Shuoyao He Yani Yang Yuqi Zeng Mengyi Xiong Ding Ding Weijun Wei Yifan Lyu Xiao-Bing Zhang Weihong Tan Microenvironment-confined kinetic elucidation and implementation of a DNA nano-phage with a shielded internal computing layer Nature Communications |
| title | Microenvironment-confined kinetic elucidation and implementation of a DNA nano-phage with a shielded internal computing layer |
| title_full | Microenvironment-confined kinetic elucidation and implementation of a DNA nano-phage with a shielded internal computing layer |
| title_fullStr | Microenvironment-confined kinetic elucidation and implementation of a DNA nano-phage with a shielded internal computing layer |
| title_full_unstemmed | Microenvironment-confined kinetic elucidation and implementation of a DNA nano-phage with a shielded internal computing layer |
| title_short | Microenvironment-confined kinetic elucidation and implementation of a DNA nano-phage with a shielded internal computing layer |
| title_sort | microenvironment confined kinetic elucidation and implementation of a dna nano phage with a shielded internal computing layer |
| url | https://doi.org/10.1038/s41467-025-56219-9 |
| work_keys_str_mv | AT decuitang microenvironmentconfinedkineticelucidationandimplementationofadnananophagewithashieldedinternalcomputinglayer AT shuoyaohe microenvironmentconfinedkineticelucidationandimplementationofadnananophagewithashieldedinternalcomputinglayer AT yaniyang microenvironmentconfinedkineticelucidationandimplementationofadnananophagewithashieldedinternalcomputinglayer AT yuqizeng microenvironmentconfinedkineticelucidationandimplementationofadnananophagewithashieldedinternalcomputinglayer AT mengyixiong microenvironmentconfinedkineticelucidationandimplementationofadnananophagewithashieldedinternalcomputinglayer AT dingding microenvironmentconfinedkineticelucidationandimplementationofadnananophagewithashieldedinternalcomputinglayer AT weijunwei microenvironmentconfinedkineticelucidationandimplementationofadnananophagewithashieldedinternalcomputinglayer AT yifanlyu microenvironmentconfinedkineticelucidationandimplementationofadnananophagewithashieldedinternalcomputinglayer AT xiaobingzhang microenvironmentconfinedkineticelucidationandimplementationofadnananophagewithashieldedinternalcomputinglayer AT weihongtan microenvironmentconfinedkineticelucidationandimplementationofadnananophagewithashieldedinternalcomputinglayer |