Chirality-Functionalized Covalent Organic Frameworks for Enantioselective Neuroprotection with Restored Neuroactive Signaling in Alzheimer’s Disease

Abstract Alzheimer’s disease (AD) is driven by amyloid-β (Aβ) accumulation and a cascade of interconnected neurotoxic events, including oxidative stress, glutamate excitotoxicity, calcium dysregulation, and impaired neuroactive ligand–receptor signaling. To address the multifactorial nature of AD pathology, chiral d- or l-cysteine-functionalized covalent organic framework (COF) nanoparticles are developed as a multitarget nanotherapeutic platform. Both enantiomers effectively inhibit Aβ aggregation, scavenge reactive oxygen species, reduce extracellular glutamate levels, and attenuate calcium dysregulation. In parallel, d/l-Cys-COFs rescue compromised neuroactive ligand–receptor signaling, as evidenced by normalized expression of neuropeptide Y and brain-derived neurotrophic factor. In transgenic AD mice, d/l-Cys-COF treatment significantly improves memory and cognitive performance. Notably, the d-enantiomer affords superior neuroprotection through enhanced suppression of pathological intracellular calcium overload, whereas restoration of neuroactive ligand–receptor signaling remains chirality-independent. These findings identify chirality as a key design element for multitarget nanotherapeutics against AD, with enantioselective efficacy arising primarily from differential regulation of calcium dysregulation and shared restoration of neuroactive signaling contributing to the overall therapeutic benefit.