{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T13:55:23Z","timestamp":1790603723488,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003995","name":"Natural Science Foundation of Anhui Province","doi-asserted-by":"publisher","award":["2208085MC51"],"award-info":[{"award-number":["2208085MC51"]}],"id":[{"id":"10.13039\/501100003995","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003995","name":"Natural Science Foundation of Anhui Province","doi-asserted-by":"publisher","award":["2208085MC74"],"award-info":[{"award-number":["2208085MC74"]}],"id":[{"id":"10.13039\/501100003995","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The genetic basis of high\u2010altitude hypoxia adaptation remains largely elusive, particularly the role of HBB. Here, we developed an integrative mesh\u2010nanorod (MN) cell sorting, chitosan nanoparticle (CS) delivery, and in vivo intraosseous (IO) injection (MN\u2022CS\u2022IO) system to functionally investigate HBB in cross\u2010species high\u2010altitude hypoxia adaptation. Using this MN\u2022CS\u2022IO platform, we transplanted high\/low\u2010altitude species HBB\u2010modified lineage\u2010negative (Lin\n                    <jats:sup>\u2212<\/jats:sup>\n                    ) cells into murine models, achieving 95.59% transfection efficiency and 8.15% HBB relative expression, and subjected them to simulated and natural Qinghai\u2010Tibet hypoxia conditions. High\u2010altitude HBB recipients exhibited downregulated Rragd expression, activated oxygen transport and hematopoietic lineage pathways, improved behavioral performance, and neuroprotection against hypoxia\u2010induced damage, compared with low\u2010altitude animals. MN\u2022CS\u2022IO system data demonstrate that HBB determines high\u2010altitude hypoxia adaptation. For validation, we generated bone marrow chimeras using CD45.1 hematopoietic cells with Pika\u2010HBB integrated at the Rosa26 locus. The reconstituted mice exhibited consistent hypoxic behavioral and phenotypic alterations with those observed via the MN\u2022CS\u2022IO system, validating the reliability and stability of HBB\u2010mediated high\u2010altitude hypoxia adaptation. Together, our findings demonstrate that HBB is a key genetic determinant of high\u2010altitude hypoxia adaptation, and also introduce a versatile gene\u2010function validation tool for evolutionary and biomedical research.\n                  <\/jats:p>","DOI":"10.1002\/advs.78002","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T13:00:18Z","timestamp":1790600418000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MN\u2022CS\u2022IO System: Cross\u2010Species Study for HBB Function in High\u2010Altitude Hypoxia Adaptation"],"prefix":"10.1002","author":[{"given":"Wenqiao","family":"Hui","sequence":"first","affiliation":[{"name":"Anhui Provincial Key Laboratory of Livestock and Poultry Product Safety Institute of Animal Husbandry and Veterinary Medicine Anhui Academy of Agriculture Sciences  Hefei China"},{"name":"Center for Stem Cell and Translational Medicine School of Life Sciences and Medical Engineering Anhui University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Mao","sequence":"additional","affiliation":[{"name":"Center for Stem Cell and Translational Medicine School of Life Sciences and Medical Engineering Anhui University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binggang","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Stem Cell and Translational Medicine School of Life Sciences and Medical Engineering Anhui University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanyue","family":"Kang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Advanced Civil Engineering Materials of Ministry of Education Key Laboratory of D&amp;A for Metal\u2010Functional Materials School of Materials Science &amp; 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Engineering Tongji University  Shanghai China"},{"name":"Center for Micro Nano Systems School of Information Science and Technology (SIST) Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yupeng","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Resources and Environment Anhui Agricultural University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2695-4737","authenticated-orcid":false,"given":"Tana","family":"Wuren","sequence":"additional","affiliation":[{"name":"Research Center for High Altitude Medicine Qinghai University  Xining China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3520-1721","authenticated-orcid":false,"given":"Qian","family":"Ban","sequence":"additional","affiliation":[{"name":"Center for Stem Cell and Translational Medicine School of Life Sciences and Medical Engineering Anhui University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4289-4754","authenticated-orcid":false,"given":"Baowei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Stem Cell and Translational Medicine School of Life Sciences and Medical Engineering Anhui University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"issue":"4929","key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1126\/science.246.4929.474","article-title":"Holocene\u2014Late Pleistocene Climatic Ice Core Records From Qinghai\u2010Tibetan Plateau","volume":"246","author":"Thompson L. 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