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Notably, most HOFs are synthesized and utilized in organic solvents, limiting their biomedical translation. Although water is a biologically compatible alternative, it competes for hydrogen bonding and disrupts interactions between building blocks, making the construction of stable aqueous HOFs challenging. Inspired by the DNA base pairing structure, the first nucleoside\u2010based HOF (N\u2010HOF\u20101) was developed using a multi\u2010hydrogen bonding strategy. This framework is synthesized entirely in water by simply mixing 2\u2010amino\u20102'\u2010fluoro\u20102'\u2010deoxyadenosine (2FA) and cyanuric acid (CA), enabling grade production while maintaining stability under physiological conditions. Microcrystal electron diffraction (MicroED) and single\u2010crystal X\u2010ray diffraction (SCXRD) studies revealed the confinement of M\u2010shaped water clusters within the channels of N\u2010HOF\u20101, mimicking DNA hydration and preserving the HOF architecture. Notably, the porous and positively charged properties of N\u2010HOF\u20101 enable interaction with bacteria to form the bacteria\u2013nanoparticle biohybrid systems. Leveraging the intrinsic bioactivity of nucleoside building blocks, this system enhances engineered bacterial colonization in the periodontium, periodontal tissue regeneration, and lymphoma therapy. These findings highlighted the potential of nucleosides as versatile building blocks for hydrophilically stable HOFs, offering new possibilities for their biomedical applications.<\/jats:p>","DOI":"10.1002\/adma.73854","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T13:28:33Z","timestamp":1782826113000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hydrophilic\u2010Stable Nucleoside\u2010Based Hydrogen\u2010Bonded Organic Frameworks (N\u2010HOF) for Therapeutic Bacterial Hybrid Systems"],"prefix":"10.1002","volume":"38","author":[{"given":"Zheng","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; Research Unit of Oral Carcinogenesis and Management &amp; Chinese Academy of Medical Sciences West China Hospital of Stomatology 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