Diazonium‐Enabled Post‐Synthetic Construction of Enantiomeric Single‐Atom Nanoagents Used for Alzheimer's Disease Treatment

Alzheimer's disease (AD) is driven by a self-amplifying interplay between oxidative stress and neuroinflammation, in which mitochondrial DNA (mtDNA) leakage-induced activation of the cGAS-STING pathway plays a central role. Strategies that solely eliminate reactive oxygen species (ROS) are insufficient to suppress downstream inflammatory cascades. Here, we report a pair of chiral dual-functional single-atom nanoagents that can simultaneously scavenge ROS and sequester leaked mtDNA. A diazonium-enabled post-synthetic modification strategy is employed to graft benzoic acid linkers onto a single-atom catalyst, enabling covalent conjugation of nona-arginine peptides with opposite chirality (L-/D-R9). The resulting constructs are further encapsulated by KLVFFAED peptides and tannic acid to yield L-/D-TKRM, conferring blood-brain barrier permeability and mitochondrial targeting. Both L- and D-TKRM effectively scavenge ROS and preserve mitochondrial function in Aβ-stimulated microglia, while D-TKRM exhibits enantioselectively prolonged mtDNA capture, more efficient suppression of cGAS-STING signaling, enhanced M2 microglial polarization, and superior neuroprotection. In vivo studies have demonstrated that these two nanoagents rescue cognitive function in 3 × Tg-AD mice, with D-TKRM showing better efficacy accompanied by reduced amyloid pathology, microglial activation, and neuronal loss. This work highlights diazonium chemistry as a new, versatile single-atom functionalization strategy and underscores that chirality is important for developing effective therapeutic agents for AD treatment.