Hydrophilic‐Stable Nucleoside‐Based Hydrogen‐Bonded Organic Frameworks (N‐HOF) for Therapeutic Bacterial Hybrid Systems

Hydrogen-bonded organic frameworks (HOFs) have emerged as promising materials for biomedical applications owing to their metal-free biocompatibility and recyclability. 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-based HOF (N-HOF-1) was developed using a multi-hydrogen bonding strategy. This framework is synthesized entirely in water by simply mixing 2-amino-2'-fluoro-2'-deoxyadenosine (2FA) and cyanuric acid (CA), enabling grade production while maintaining stability under physiological conditions. Microcrystal electron diffraction (MicroED) and single-crystal X-ray diffraction (SCXRD) studies revealed the confinement of M-shaped water clusters within the channels of N-HOF-1, mimicking DNA hydration and preserving the HOF architecture. Notably, the porous and positively charged properties of N-HOF-1 enable interaction with bacteria to form the bacteria-nanoparticle 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.