Ultrathin 2D Multivariate Hydrogen‐Bonded Organic Framework Nanosheets for Fluorescent DNA Sensing

The multivariate strategy is generally incompatible with densely packed structures, as this approach typically requires porous frameworks to manage the steric demands of incorporated functional groups. Without sufficient free volume, the frameworks are prone to structural transformations driven by steric hindrance. Here, we demonstrate that this limitation can be overcome by exploiting an interaction hierarchy in hydrogen-bonded organic frameworks (HOFs), where strong directional charge-assisted hydrogen bonds define the framework while weaker interactions accommodate steric perturbations. This enables the extension of the multivariate strategy to densely packed systems, yielding multivariate HOFs with well-defined structures and tailored functionalities. Specifically, a carboxylate-amidinium-based layered HOF (HOF-FAFU-4) was synthesized as a prototype platform. It enables the integration of diverse building blocks and precise tuning of the spatial arrangement of functional groups. Benefiting from their layered structure, these materials can be further exfoliated into ultrathin 2D nanosheets, thereby enhancing the accessibility of functional sites. These ultrathin 2D nanosheets serve as fluorescent sensing platforms for DNA detection, achieving a limit of detection (LOD) of 8.1 pM and demonstrating broad generality for multiple DNA analytes. This work not only broadens the scope of the multivariate strategy but also expands the structural diversity and applicability of HOFs.