ABSTRACT
Bioenergetic deficits, such as mitochondrial impairments and dysfunction in glucose metabolism, have been identified as significant contributors to neurodegenerative diseases. Nevertheless, identifying safe and effective means to address intracellular bioenergetic deficits remains a significant challenge. This work provides mechanistic insights into the bioenergetic metabolism-regulating function of a suspension of gold (Au) nanocrystals, referred to as CNM-Au8®, that are synthesized electrochemically in the absence of any surface-capping organic ligands. When neurons are subjected to excitotoxic stressors or toxic peptides, treatment of neurons with CNM-Au8 results in dose-dependent neuronal survival and preservation of neurite networks across multiple neuronal subtypes. CNM-Au8 efficiently catalyzes the conversion of an energetic co-factor, nicotinamide adenine dinucleotide hydride (NADH), into its oxidized, dehydrogenated counterpart (NAD+), which triggers an increase in energy production in the form of adenosine triphosphate (ATP). Detailed kinetic measurements reveal that CNM-Au8-catalyzed NADH oxidation obeys Michaelis-Menten kinetics and exhibits pH-dependent kinetic profiles. CNM-Au8 functions as an NADH-dehydrogenase-mimicking nanozyme that effectively regulates intracellular bioenergetic metabolism. We further utilize photoexcited charge carriers and photothermal transduction, which can be generated through optical excitations of the plasmonic electron oscillations or the interband electronic transitions in CNM-Au8, as unique leverages to modulate reaction kinetics. Benefiting from their bio-compatibility, blood-brain barrier penetrance, tunable optical properties, and enzyme-mimicking functions, CNM-Au8 nanocrystals with deliberately tailored structures and surfactant-free clean surfaces hold great promise for developing next-generation therapeutic agents for neurodegenerative diseases.
Competing Interest Statement
Z.W., L.T., and H.W. declare no competing financial interest. K.S.H., M.T.H., and M.G.M. are full time employees of Clene Nanomedicine, Inc. and own shares in the company. A.H., L.R., and N.C. are full-time employees of Neuro-Sys, a private contract research organization. R.R. is the co-founding CEO and CSO of CELLOMET, a private contract research organization.
