Facilitating Pro-survival Mitophagy for Alleviating Parkinson’s Disease via Sequence-Targeted Lycopene Nanodots

Abstract

The pathogenesis of Parkinson’s disease is closely linked to impaired mitochondrial function and abnormal mitophagy. Biocompatible natural antioxidants effectively protect dopaminergic neurons. However, the main challenge in using natural antioxidants for Parkinson’s disease therapy is creating a delivery platform to achieve neuron-targeted enrichment. Herein, we synthesized rationally sequence-targeted lycopene nanodots using recombinant human H-ferritin nanocages with lycopene loading into the cavity and lipophilic triphenylphosphonium (TPP) coupling on the outer surface. The nanodots allow for the neural enrichment and mitochondrial regulation of lycopene through blood–brain barrier transcytosis and neuronal mitochondria-targeting capability. These anti-ROS nanodots protect neuronal mitochondrial function and promote PINK1/Parkin-mediated mitophagy in MPTP toxicity-induced neurons in vivo and in vitro, which favors the secretory efflux of pathogenic α-synuclein and the survival of dopaminergic neurons. Moreover, these nanodots restore the Parkinson-like motor symptoms in Parkinson’s model mice. This noninvasive sequence-targeted delivery strategy with excellent biocompatibility for pro-survival mitophagy-mediated pathology alleviation makes it a promising approach for treating and preventing Parkinson’s disease.

Orally administered dual-targeted astaxanthin nanoparticles as novel dietary supplements for alleviating hepatocyte oxidative stress

“…Pearson's coefficients of Nile Red@WPI-GOS/TPP-WPI-GOS were 0.55 and 0.65 at 2 h, and 0.62 and 0.76 at 4 h, respectively. Xia et al 36 reported achieving targeted delivery to neuronal mitochondria by encapsulating lycopene within the cavity of TPP-modified recombinant human H-ferritin nanocages, facilitating neuronal enrichment and mitochondrial regulation of lycopene. These results confirmed that the AXT@TPP-WPI-GOS nanoparticles could target liver parenchymal cells and thus improve the precise bio-utilization of AXT.…”

Advancements of the Molecular Directed Design and Structure–Activity Relationship of Ferritin Nanocage

“…The encapsulation strategies used include pH-responsive reversible self-assembly, urea-mediated encapsulation, channel-oriented encapsulation, and coencapsulation methods . Ferritin has successfully loaded various natural active molecules such as anthocyanins, curcumin, β-carotene, lycopene, and rutin etc. ,− These molecules are used to enhance water solubility, stability, bioavailability, and target specificity of the cargo. For example, water-soluble chitosan–ferritin–baicalein nanoparticles prepared from alfalfa-derived phytoferritin nanocages are loaded with 52 molecules of baicalein and improve the bioavailability of baicalein by prolonging the release time of baicalein during gastrointestinal digestion .…”

The role of mitophagy in metabolic diseases and its exercise intervention

“…1) The ubiquitin-dependent pathway refers to the extensive ubiquitination of proteins that depend on the surface of the mitochondrion to promote mitophagy. The PINK1/Parkin is a critical mediator in the classical mitophagy pathway and has been extensively studied ( Han H. et al, 2023 ; Xia et al, 2023 ). Under physiological conditions, cytoplasmically synthesized PINK1 first interacts with the translocase of the outer membrane (TOM) to enter the mitochondrial membrane gap ( Kato et al, 2013 ).…”