Improving mitochondrial function for alleviating memory decline of aging mice via dual-delivering lycopene nanoparticles

Natural antioxidants as safe and efficient agents play great effects on neurodegenerative diseases. However, their potential has been limited due to weak bioavailability and a low brain-blood ratio. Herein, protein construction strategy and nanotechnology are united to design dual-delivering lycopene (LYC) nanoparticles with the blood-brain barrier crossing and intra-neuronal mitochondria targeting capabilities, supported by brain transcytosis H-ferritin nanocage with LYC loaded into its cavity and lipophilic triphenylphosphonium (TPP) coupled on it. The neuroprotection of TPP-rHuHF-LYC nanoparticles was significantly observed: (i) regulating the mitochondrial function in nerve cells via improving energy production, maintaining DNA copy number, avoiding excessive opening of permeability transition pores and keeping the intact morphology of mitochondria; (ii) rescuing the memory decline of aging mice via the protection of synaptic mitochondria; (iii) enhancing synaptic plasticity in hippocampal neurons of mice via activating PKA/CREB/BNDF long-term potentiation pathway. This study provides a novel design strategy for intracerebral delivery and intra-neuronal mitochondrial-targeted therapy of natural antioxidant nanomedicine to treat neuronal dysfunction and memory loss.