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In Alzheimer's disease (AD), elevated hydrogen peroxide (H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    ) accompanies hallmark features, including amyloid\u2010\u03b2 (A\u03b2) aggregate deposition and metal ion dyshomeostasis, creating an oxidative milieu primed for selective chemical activation. Here, we show a rationally designed prodrug platform that harnesses H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    as an endogenous trigger for redox\u2010based therapy. Boronic ester\u2010masked precursors (\n                    <jats:bold>BE\u20101<\/jats:bold>\n                    and\n                    <jats:bold>BE\u20102<\/jats:bold>\n                    ) remain inert under physiological conditions but undergo rapid oxidative deboronation in the presence of H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    , releasing redox\u2010active aminophenols. These activated molecules exhibit multimodal pathological modulation, as revealed by molecular\u2010level biochemical and biophysical analyses: scavenging reactive oxygen species, inducing residue\u2010specific oxidative modifications of A\u03b2, and redirecting aggregation pathways of both metal\u2010free and metal\u2010bound A\u03b2. In AD transgenic mice,\n                    <jats:bold>BE\u20101<\/jats:bold>\n                    undergoes conversion to its active form within the brain tissue. Long\u2010term administration of\n                    <jats:bold>BE\u20101<\/jats:bold>\n                    markedly reduces hippocampal oxidative stress, lowers amyloid plaque burden, and improves cognitive performance. This pathology\u2010responsive, activity\u2010based prodrug strategy provides a chemically precise framework for simultaneously modulating multiple, interconnected drivers of neurodegeneration.\n                  <\/jats:p>","DOI":"10.1002\/smll.74013","type":"journal-article","created":{"date-parts":[[2026,5,31]],"date-time":"2026-05-31T09:55:33Z","timestamp":1780221333000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Prodrug Approach for Activity\u2010Based Chemical Modulation toward Multiple Pathological Targets in Alzheimer's Disease"],"prefix":"10.1002","volume":"22","author":[{"given":"Jimin","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Chemistry Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunseo","family":"Hong","sequence":"additional","affiliation":[{"name":"Department 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