Near-Infrared Responsive Dopamine/Melatonin-Derived Nanocomposites Abrogating in Situ Amyloid β Nucleation, Propagation, and Ameliorate Neuronal Functions

Alzheimer's disease (AD) is one of the common causes of dementia and mild cognitive impairments, which is progressively expanding among the elderly population worldwide. A short Amyloid-β (Aβ) peptide generated after amyloidogenic processing of amyloid precursor protein exist as intermolecular β-sheet rich oligomeric, protofibriler, and fibrillar structures and believe to be toxic species which instigate neuronal pathobiology in the brain and deposits as senile plaque. Enormous efforts are being made to develop an effective anti-AD therapy that can target Aβ processing, aggregation, and propagation and provide a synergistic neuroprotective effect. However, a nanodrug prepared from natural origin can confer a multimodal synergistic chemo/photothermal inhibition of Aβ pathobiology is not yet demonstrated. In the present work, we report a dopamine-melatonin nanocomposite (DM-NC), which possesses a synergistic near-infrared (NIR) responsive photothermal and pharmacological modality. The noncovalent interaction-mediated self-assembly of melatonin and dopamine oxidative intermediates leads to the evolution of DM-NCs that can withstand variable pH and peroxide environment. NIR-activated melatonin release and photothermal effect collectively inhibit Aβ nucleation, self-seeding, and propagation and can also disrupt the preformed Aβ fibers examined using in vitro Aβ aggregation and Aβ-misfolding cyclic amplification assays. The DM-NCs display a higher biocompatibility to neuroblastoma cells, suppress the AD-associated generation of intracellular reactive oxygen species, and are devoid of any negative impact on the axonal growth process. In okadaic acid-induced neuroblastoma and ex vivo midbrain slice culture-based AD model, DM-NCs exposure suppresses the intracellular Aβ production, aggregation, and accumulation. Therefore, this nature-derived nanocomposite demonstrates a multimodal NIR-responsive synergistic photothermal and pharmacological modality for effective AD therapy.