Homocysteine‐Responsive Covalent Organic Frameworks as Signaling Scaffolds: Modulating Transsulfuration for Depression Treatment

Abstract Depression is a significant global health concern with limited effective treatment strategies to date. Elevated homocysteine is identified as a critical factor contributing to the severity of depression by aggravating neuroinflammation. Herein, this study develops a diverse array of homocysteine‐stimulated responsive covalent organic frameworks (COFs) as novel therapeutic agents. Using Schiff‐base condensation reactions between cystamine/selenocystamine and various C₂‐ and C₃‐symmetric aryl aldehydes, it successfully synthesized a library of 20 COFs. The sensitivity and specificity of the resultant COFs for homocysteine clearance are validated using serum samples from patients with depression and a mouse model. Non‐targeted metabolomics and transcriptomics analyses revealed that these COFs not only exogenously and directly scavenge homocysteine but also synergistically enhance the transsulfuration pathway within the endogenous metabolic cycle for efficient clearance. Furthermore, these COFs mitigated neuroinflammation by inhibiting inflammatory responses, scavenging reactive oxygen species, and modulating neuronal and microglial activity. They also activated neuroactive ligand‐receptor signaling pathways and preserved mitochondrial function, thereby maintaining oxidative phosphorylation. Collectively, these mechanisms resulted in significant improvements in anxiety and depressive behaviors in mice. This study pioneers the therapeutic application of homocysteine‐responsive COFs for depression treatment, opening up tremendous opportunities for the biomedical applications of COFs.