Positional isomerism offers a powerful strategy to fine-tune molecular reactivity toward diverse pathogenic factors in complex diseases. Here, we show that positional isomerism in phenylene-based compact molecules bearing electron-donating groups at the <i>para</i>, <i>ortho</i>, or <i>meta</i> positions engineers distinct chemical reactivities with key pathological targets, including reactive oxygen species, metal-free amyloid-β (Aβ), and metal-bound Aβ, which are implicated in Alzheimer's disease (AD). Comprehensive mechanistic analyses reveal that specific isomers drive covalent adduct formation, oxidation, and oxidative cleavage toward metal-free and metal-bound Aβ, with their chemical transformations governed by electronic and metal-binding properties dictated by the substitution pattern. In AD transgenic mice, <i>para</i>- and <i>ortho</i>-substituted analogs display markedly different efficacies in attenuating hippocampal oxidative stress, lowering amyloid plaque burden, and improving cognitive performance. Our findings establish a structure-property-reactivity framework in which subtle positional changes elicit divergent chemical and biological outcomes, providing a principle for rationally designing multi-target-directed chemical modulators to probe and control multifactorial networks underlying neurodegeneration.

DNA is an anisotropic, water-attracting, and biocompatible material, an ideal building block for hydrogel. The alignment of the anisotropic DNA chains is essential to maximize hydrogel properties, which has been little explored. Here, we present a method to fabricate the anisotropic DNA hydrogel that allows precise control for the polymerization process of photoreactive cationic monomers. Scanning ultraviolet light enables the uniaxial alignment of DNA chains through the polymerization-induced diffusive mass flow using a concentration gradient. While studying anisotropic mechanical properties and orientation recovery according to the DNA chain alignment direction, we demonstrate the potential of directionally controlled DNA hydrogels as smart materials.

Positional isomerism offers a powerful strategy to fine-tune molecular reactivity toward diverse pathogenic factors in complex diseases. Here, we show that positional isomerism in phenylene-based compact molecules bearing electron-donating groups at the <i>para</i>, <i>ortho</i>, or <i>meta</i> positions engineers distinct chemical reactivities with key pathological targets, including reactive oxygen species, metal-free amyloid-β (Aβ), and metal-bound Aβ, which are implicated in Alzheimer's disease (AD). Comprehensive mechanistic analyses reveal that specific isomers drive covalent adduct formation, oxidation, and oxidative cleavage toward metal-free and metal-bound Aβ, with their chemical transformations governed by electronic and metal-binding properties dictated by the substitution pattern. In AD transgenic mice, <i>para</i>- and <i>ortho</i>-substituted analogs display markedly different efficacies in attenuating hippocampal oxidative stress, lowering amyloid plaque burden, and improving cognitive performance. Our findings establish a structure-property-reactivity framework in which subtle positional changes elicit divergent chemical and biological outcomes, providing a principle for rationally designing multi-target-directed chemical modulators to probe and control multifactorial networks underlying neurodegeneration.

DNA is an anisotropic, water-attracting, and biocompatible material, an ideal building block for hydrogel. The alignment of the anisotropic DNA chains is essential to maximize hydrogel properties, which has been little explored. Here, we present a method to fabricate the anisotropic DNA hydrogel that allows precise control for the polymerization process of photoreactive cationic monomers. Scanning ultraviolet light enables the uniaxial alignment of DNA chains through the polymerization-induced diffusive mass flow using a concentration gradient. While studying anisotropic mechanical properties and orientation recovery according to the DNA chain alignment direction, we demonstrate the potential of directionally controlled DNA hydrogels as smart materials.

The deposition of amyloid-β (Aβ) aggregates and metal ions within senile plaques is a hallmark of Alzheimer's disease (AD). Among the modifications observed in Aβ peptides, <i>N</i>-terminal truncation at Phe4, yielding Aβ_4-x, is highly prevalent in AD-affected brains and significantly alters Aβ's metal-binding and aggregation profiles. Despite the abundance of Zn(II) in senile plaques, its impact on the aggregation and toxicity of Aβ_4-x remains unexplored. Here, we report the distinct aggregation behavior of <i>N</i>-terminally truncated Aβ, specifically Aβ_4-42, in the absence and presence of either Zn(II), Aβ seeds, or both, and compare it to that of full-length Aβ_1-42. Our findings reveal notable differences in the aggregation profiles of Aβ_4-42 and Aβ_1-42, largely influenced by their different Zn(II)-binding properties. These results provide insights into the mechanisms underlying the distinct aggregation behavior of truncated and full-length Aβ in the presence of Zn(II), contributing to a deeper understanding of AD pathology.

The fabrication of liquid crystalline (LC) organogel via supramolecular interactions between Deoxyribonucleic acid (DNA) and lyotropic cationic surfactant containing cyanobiphenyl moiety is reported. The fabricated organogel endows dominantly viscous behavior in dimethyl sulfoxide (DMSO) and elastic behavior in n-propanol (n-PrOH), respectively. By judiciously controlling the viscosity, DMSO organogels can be drawn to form a fiber with an elongation of up to 4.6 × 10³%, emphasizing extraordinary stretchability. Higher-order structures, such as yarn and a co-alignment matrix for anisotropic particles, can be produced by assembling a single fiber. On the other hand, free-standing n-PrOH organogels demonstrate a remarkable storage modulus of 10⁵ Pa and manifest self-healing properties. Finally, a sustainable method by transforming n-PrOH gel into an aerogel through critical point drying (CPD), enabling its use as an adsorbent while simultaneously enhancing its reusability is proposed. It is envisaged that these DNA-based organogels, through conceivable combinations between DNA as a building block and cationic surfactant with functionalities as a counterpart, will contribute to significant progress in DNA-based multi-functional organogels.