A Prodrug Approach for Activity‐Based Chemical Modulation toward Multiple Pathological Targets in Alzheimer's Disease

ABSTRACT Targeting disease‐specific chemical signals enables precise therapeutic control over complex pathologies. In Alzheimer's disease (AD), elevated hydrogen peroxide (H ₂ O ₂ ) accompanies hallmark features, including amyloid‐β (Aβ) 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 ₂ O ₂ as an endogenous trigger for redox‐based therapy. Boronic ester‐masked precursors ( BE‐1 and BE‐2 ) remain inert under physiological conditions but undergo rapid oxidative deboronation in the presence of H ₂ O ₂ , releasing redox‐active aminophenols. These activated molecules exhibit multimodal pathological modulation, as revealed by molecular‐level biochemical and biophysical analyses: scavenging reactive oxygen species, inducing residue‐specific oxidative modifications of Aβ, and redirecting aggregation pathways of both metal‐free and metal‐bound Aβ. In AD transgenic mice, BE‐1 undergoes conversion to its active form within the brain tissue. Long‐term administration of BE‐1 markedly reduces hippocampal oxidative stress, lowers amyloid plaque burden, and improves cognitive performance. This pathology‐responsive, activity‐based prodrug strategy provides a chemically precise framework for simultaneously modulating multiple, interconnected drivers of neurodegeneration.