Abstract Template method offers a promising strategy for synthesizing large pore inaccessible through traditional molecular design. However, this approach has not yet been successfully implemented in molecular assemblies based on weak non-covalent interactions (NCIs), mainly because the assemblies often deviate from original structures during template-assisted syntheses, and the resulting porous structures lack the robustness to survive upon template removal. In this work, we address these challenges through choosing small biocompatible building blocks featuring multiple hydrogen-bonded sites and extensive π conjugation, enabling self-assembly into desired structure in the presence of templates and ensure structural integration upon template removal. As a result, the transformation from densely packed hydrogen-bonded crystalline materials to macroporous structure, referred to as hydrogen-bonded organic frameworks (HOFs), becomes achievable. This strategy facilitates the fabrication of highly ordered materials in single-crystal form with high physiological stability, and enhanced mass transfer. Importantly, it greatly broadens the HOF library to small, affordable, low-toxic, and clinically applicable molecules, making HOFs promising biocompatible porous substrates for bio-related applications such as enzyme immobilization. Herein, we successfully loaded trypsin into macroporous HOFs, which function as effective cellular scaffolds and promote the differentiation of peripheral blood mononuclear cells into fibrocytes, demonstrating their promising potential for biologic applications.
Li et al. (2025) studied this question.