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Hypotonic encapsulation is the most widely employed technique; however, the correlation between nanoparticle sizes and the hypotonic osmolarities required for efficient encapsulation remains unclear. In this study, the size\u2010dependent osmolarity requirements governing nanoparticles into RBCs are investigated. Using monodisperse gold nanoparticles as model systems, the optimal osmolarity correlated with nanoparticle diameter is identified as 150 mOsm for particles \u226433\u00a0nm, 100 mOsm for particles 66\u201391\u00a0nm, and 50 mOsm for particles \u2248133\u00a0nm. These conditions maximized encapsulation efficiency while maintaining RBC membrane integrity and preserving the expression of key surface proteins, including CD47. The applicability of this approach is further validated using nanoparticles of diverse compositions and zeta potentials. In vitro assays demonstrated minimal hemolysis and significantly reduced macrophage uptake across all formulations. Complementary in vivo imaging reveals prolonged systemic circulation and biodistribution profiles that closely resemble those of native RBCs. This study establishes a standardized, size\u2010adaptive hypotonic encapsulation protocol, offering a versatile and scalable platform for engineering RBC\u2010based carriers with broad translational potential in nanomedicine.<\/jats:p>","DOI":"10.1002\/smtd.202501437","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T06:47:36Z","timestamp":1765608456000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Osmolarity\u2010Directed Encapsulation of Size\u2010Tuned Nanoparticles into Red Blood Cells"],"prefix":"10.1002","volume":"10","author":[{"given":"Shihao","family":"Bai","sequence":"first","affiliation":[{"name":"Ningbo Key Laboratory of Biomedical Imaging Probe Materials and Technology Zhejiang International Cooperation Base of Biomedical Materials Technology and Application Chinese Academy of Sciences (CAS) Key Laboratory of Magnetic Materials and Devices Zhejiang Engineering Research Center for Biomedical Materials at Ningbo Cixi Institute of Biomedical Engineering, Institute of Biomedical Engineering at Ningbo Institute of Materials Technology and Engineering Chinese Academy of Sciences  Ningbo 315201..."},{"name":"University of Chinese Academy of Sciences  Beijing 100049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiying","family":"Hou","sequence":"additional","affiliation":[{"name":"Ningbo Key Laboratory of Biomedical Imaging Probe Materials and Technology Zhejiang International Cooperation Base of Biomedical Materials Technology and Application Chinese Academy of Sciences (CAS) Key Laboratory of Magnetic Materials and Devices Zhejiang Engineering Research Center for Biomedical Materials at Ningbo Cixi Institute of Biomedical Engineering, Institute of Biomedical Engineering at Ningbo Institute of Materials Technology and Engineering Chinese Academy of Sciences  Ningbo 315201..."},{"name":"University of Chinese Academy of 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of Biomedical Materials Technology and Application Chinese Academy of Sciences (CAS) Key Laboratory of Magnetic Materials and Devices Zhejiang Engineering Research Center for Biomedical Materials at Ningbo Cixi Institute of Biomedical Engineering, Institute of Biomedical Engineering at Ningbo Institute of Materials Technology and Engineering Chinese Academy of Sciences  Ningbo 315201..."},{"name":"University of Chinese Academy of Sciences  Beijing 100049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Lin","sequence":"additional","affiliation":[{"name":"Ningbo Key Laboratory of Biomedical Imaging Probe Materials and Technology Zhejiang International Cooperation Base of Biomedical Materials Technology and Application Chinese Academy of Sciences (CAS) Key Laboratory of Magnetic Materials and Devices Zhejiang Engineering Research Center for Biomedical Materials at Ningbo Cixi Institute of Biomedical Engineering, Institute of Biomedical Engineering at Ningbo Institute of Materials Technology and Engineering Chinese Academy of Sciences  Ningbo 315201..."},{"name":"University of Chinese Academy of Sciences  Beijing 100049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8137-7894","authenticated-orcid":false,"given":"Changyong","family":"Gao","sequence":"additional","affiliation":[{"name":"Ningbo Key Laboratory of Biomedical Imaging Probe Materials and Technology Zhejiang International Cooperation Base of Biomedical Materials Technology and Application Chinese Academy of Sciences (CAS) Key Laboratory of Magnetic Materials and Devices Zhejiang Engineering Research Center for Biomedical Materials at Ningbo Cixi Institute of Biomedical Engineering, Institute of Biomedical Engineering at Ningbo Institute of Materials Technology and Engineering Chinese Academy of Sciences  Ningbo 315201..."},{"name":"University of Chinese Academy of Sciences  Beijing 100049 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