Inhibition of the cGAS–STING pathway via an endogenous copper ion-responsive covalent organic framework nanozyme for Alzheimer's disease treatment†

Inhibition of cGAS–STING overactivation has recently emerged as a promising strategy to counteract Alzheimer's disease (AD). However, current cGAS–STING inhibitors as immunosuppressants suffer from instability, non-specific targeting, and innate immune disruption. Here, an endogenous AD brain copper ion-responsive covalent organic framework (COF)-based nanozyme (denoted as TP@PB-COF@NADH) has been designed for targeted inhibition of the cGAS–STING pathway for AD treatment. The effective trapping of excess brain endogenous copper ions by TP@PB-COF@NADH not only inhibits the Cu²⁺-induced harmful reactive oxygen species (ROS) production which is one of the mediators of cGAS–STING activation, but also activates the nanozyme activity of TP@PB-COF@NADH. Furthermore, the well-prepared nanozyme catalytically generates NAD⁺ and consumes hydrogen peroxide (H₂O₂) through second near-infrared (NIR-II) enhanced nicotinamide adenine dinucleotide (NADH) peroxidase (NPX)-like activity, realizing the efficient inhibition of the cGAS–STING pathway and associated neuroinflammation. Moreover, replenishing NAD⁺ levels efficiently restores mitochondrial function and ATP supply. In vivo studies demonstrate that TP@PB-COF@NADH with NIR-II irradiation significantly improves cognitive function in 3× Tg-AD mice, with a reduction in amyloid-β (Aβ) plaque, neuroinflammation and neuronal damage. Collectively, this work presents a promising approach for AD treatment by using an AD brain harmful excess endogenous copper ion-responsive and efficient nanozyme.