Chiral Supramolecular Hydrogen Bonding Networks for Enantio‐Selective Catalysis Against Neuroinflammation

Abstract

ABSTRACT Non‐covalent interactions are critical for regulating protein stability, reshaping catalytic active sites, and facilitating enzymatic reactions. Introducing these interactions into reticular materials offers a new approach to constructing artificial enzymes and more closely mimicking the catalytic microenvironment. Herein, a pair of chiral hydrogen‐bonded organic frameworks (LHOF and DHOF) has been constructed, and their unique crystal structures have been determined. These porous chiral HOFs act as substrate enrichment pockets, active cavities, and possess aldolase‐like activity, which can catalyze the asymmetric synthesis of the enantiomeric bioactive molecule, 3‐hydroxy‐1,5‐diphenyl‐1‐pehtanone. Compared to the right‐handed enantiomer, the left‐handed compound shows superior reactive oxygen species (ROS) scavenging capability in an LPS‐induced inflammatory model. Further studies demonstrate that the anti‐neuroinflammatory effect of this chiral product can reverse microglia phenotype, thereby enhancing their Aβ phagocytosis and alleviating Alzheimer's disease symptoms in the 3×Tg‐AD mouse model. Thus, introduction of non‐covalent interactions into reticular materials enhances enzyme‐mimicking technology and offers new insights into enantioselective in vivo catalysis. This work provides a new paradigm for developing bioinspired materials chemistry and exploring their applications in enantioselective biomimetic catalysis.