Multifunctional bioreactive-nanoconstructs for sensitive and accurate MRI of cerebrospinal fluid pathology and intervention of Alzheimer's disease.

• A novel multifunctional and bioreactive nanoconstruct (NC) system is designed and synthesized by self-assembly in one-pot. • The NCs efficiently cross the blood-brain barrier and target amyloid-β and oxidative stress-affected AD brain regions. • The NCs enhance MRI contrast enabling non-invasive early detection of CSF pathology with high sensitivity and accuracy. • The NCs facilitate oxygenation, reduce oxidative stress and pro-inflammatory cytokines, and increase neuron survival. Lack of sensitive detection of early onset and progression of Alzheimer's disease (AD) by non-invasive methods limits the development and implementation of therapeutic interventions. Given that cerebral oxidative stress and inflammation occur before diagnosable clinical symptoms, a multifunctional theranostic nanoconstruct (NC) system has been developed. It gains entry to the brain by a targeting moiety, binds selectively with soluble amyloid-β (Aβ) and Aβ plagues via a conjugated anti-Aβ antibody. The NC is activated by endogenous reactive oxygen species (ROS), enhancing magnetic resonance (MR) contrast signals in disease-affected areas. It exhibits superior performance in detecting cerebrospinal fluid (CSF) pathology in an AD mouse model by MR imaging. Intravenously injected NCs significantly amplify T1-weighted MR signals in the CSF by 1.51–2.24 fold, nearly proportional to cerebral concentrations of ROS and pro-inflammatory cytokine interleukin-1β (IL-1β). The NC-enhanced CSF MR signals demonstrate high detection sensitivity (88.9 %) and specificity (100 %) even at early-stage AD. Moreover, the NCs protected primary cortical neurons from oxidative stress in vitro and reduce cerebral ROS and IL-1β levels in AD mice by 36 %–83 %. This multifunctional NC-based technology may allow for early detection and treatment of AD prior to cognitive decline when therapies may prove more beneficial. [ABSTRACT FROM AUTHOR]