{"title":"HDX-MS reveals pH and temperature-responsive regions on AAV capsids and the structural basis for DNA release.","authors":"Xiang Ye, Mengqi Hu, Yunli Hu, Haibo Qiu, Ning Li","doi":"10.1038/s41434-025-00539-4","DOIUrl":null,"url":null,"abstract":"<p><p>Recombinant adeno-associated viruses (AAVs) have become increasingly popular as gene therapy vectors in recent years. Like all viruses, AAVs undergo dynamic structural changes in response to varying temperature and pH conditions. However, the specific capsid regions involved in these processes remain unknown. In this study, we employed Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS) to investigate the impact of pH and temperature on the structure and conformational dynamics of AAV capsids. Our analysis identified specific regions of the capsid that are sensitive to these environmental changes. Additionally, our data elucidated the structural basis for DNA uncoating or leakage triggered by low pH or high temperature. Detailed structural characterization of AAVs by HDX-MS in this study deepens our understanding of viral capsid conformational dynamics and stability in AAV transduction and manufacturing and storage conditions, paving the way for formulation development and next-generation capsid engineering.</p>","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6000,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Gene Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41434-025-00539-4","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Recombinant adeno-associated viruses (AAVs) have become increasingly popular as gene therapy vectors in recent years. Like all viruses, AAVs undergo dynamic structural changes in response to varying temperature and pH conditions. However, the specific capsid regions involved in these processes remain unknown. In this study, we employed Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS) to investigate the impact of pH and temperature on the structure and conformational dynamics of AAV capsids. Our analysis identified specific regions of the capsid that are sensitive to these environmental changes. Additionally, our data elucidated the structural basis for DNA uncoating or leakage triggered by low pH or high temperature. Detailed structural characterization of AAVs by HDX-MS in this study deepens our understanding of viral capsid conformational dynamics and stability in AAV transduction and manufacturing and storage conditions, paving the way for formulation development and next-generation capsid engineering.
期刊介绍：
Gene Therapy covers both the research and clinical applications of novel therapeutic techniques based on a genetic component. Over the last few decades, significant advances in technologies ranging from identifying novel genetic targets that cause disease through to clinical studies, which show therapeutic benefit, have elevated this multidisciplinary field to the forefront of modern medicine.
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