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Strategies that solely eliminate reactive oxygen species (ROS) are insufficient to suppress downstream inflammatory cascades. Here, we report a pair of chiral dual\u2010functional single\u2010atom nanoagents that can simultaneously scavenge ROS and sequester leaked mtDNA. A diazonium\u2010enabled post\u2010synthetic modification strategy is employed to graft benzoic acid linkers onto a single\u2010atom catalyst, enabling covalent conjugation of nona\u2010arginine peptides with opposite chirality (L\u2010\/D\u2010R9). The resulting constructs are further encapsulated by KLVFFAED peptides and tannic acid to yield L\u2010\/D\u2010TKRM, conferring blood\u2010brain barrier permeability and mitochondrial targeting. Both L\u2010 and D\u2010TKRM effectively scavenge ROS and preserve mitochondrial function in A\u03b2\u2010stimulated microglia, while D\u2010TKRM exhibits enantioselectively prolonged mtDNA capture, more efficient suppression of cGAS\u2013STING signaling, enhanced M2 microglial polarization, and superior neuroprotection. In vivo studies have demonstrated that these two nanoagents rescue cognitive function in 3 \u00d7 Tg\u2010AD mice, with D\u2010TKRM showing better efficacy accompanied by reduced amyloid pathology, microglial activation, and neuronal loss. This work highlights diazonium chemistry as a new, versatile single\u2010atom functionalization strategy and underscores that chirality is important for developing effective therapeutic agents for AD treatment.<\/jats:p>","DOI":"10.1002\/smll.74610","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T12:47:55Z","timestamp":1785242875000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Diazonium\u2010Enabled Post\u2010Synthetic Construction of Enantiomeric Single\u2010Atom Nanoagents Used for Alzheimer's Disease Treatment"],"prefix":"10.1002","volume":"22","author":[{"given":"Junlin","family":"Ya","sequence":"first","affiliation":[{"name":"Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization Changchun Institute of Applied Chemistry Chinese Academy of Sciences  Changchun Jilin China"},{"name":"School of Applied Chemistry and Engineering 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