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...

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Main Authors: Decui Tang, Shuoyao He, Yani Yang, Yuqi Zeng, Mengyi Xiong, Ding Ding, Weijun Wei, Yifan Lyu, Xiao-Bing Zhang, Weihong Tan
Format: Article
Language:English
Published: Nature Portfolio 2025-01-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-56219-9
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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.
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institution Kabale University
issn 2041-1723
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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
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