Neuronal mitochondria-targeted therapy for Alzheimer’s disease by systemic delivery of resveratrol using dual-modified novel biomimetic nanosystems

Abstract

Reactive oxygen species (ROS)-induced neuronal mitochondrial dysfunction is a key pathologic factor in sporadic Alzheimer's disease (AD). Neuronal mitochondria have been proposed to be a promising therapeutic target for AD, especially for the failures of phase III clinical trials on conventional amyloidb (Ab) targeted therapy. However, the efficient intravenous delivery of therapeutic agents to neuronal mitochondria in the brain remains a major challenge due to the complicated physiological environment. Recently, biomaterials-based nanomedicine has been widely investigated for the treatment of AD. Herein, we devised a strategy for functional antioxidant delivery to neuronal mitochondria by loading antioxidants into red blood cell (RBC) membrane-coated nanostructured lipid carriers (NLC) bearing rabies virus glycoprotein (RVG29) and triphenylphosphine cation (TPP) molecules attached to the RBC membrane surface (RVG/TPP NPs@RBCm). With the advantage of suitable physicochemical properties of NLC and unique biological functions of the RBC membrane, RVG/TPP NPs@RBCm are stabilized and enabled sustained drug release, providing improved biocompatibility and long-term circulation. Under the synergistic effects of RVG29 and TPP, RVG/TPP NPs@RBCm can not only penetrate the blood-brain barrier (BBB) but also target neuron cells and further localize in the mitochondria. After encapsulating Resveratrol (RSV) as the model antioxidant, the data demonstrated that RVG/TPP-RSV NPs@RBCm can relieve AD symptoms by mitigating Ab-related mitochondrial oxidative stress both in vitro and in vivo. The memory impairment in APP/PS1 mice is significantly improved following the systemic administration of RVG/TPP-RSV NPs@RBCm. In conclusion, intravenous neuronal mitochondria-targeted dual-modified novel biomimetic nanosystems are a promising therapeutic candidate for ROS-induced mitochondrial dysfunction in AD.

Macrophage membrane-coated nanocarriers Co-Modified by RVG29 and TPP improve brain neuronal mitochondria-targeting and therapeutic efficacy in Alzheimer's disease mice

“…The abnormal function of mitochondria and the aggregation of aβ will lead to the apoptosis of neurons lacking regeneration ability [ 9 ]. Recent studies have treated neuronal mitochondria dysfunction as a new therapeutic target for AD [ 10 , 11 ].…”

“…Recently, bioinspired strategies are gaining attention for drug delivery application because the nanoparticles are engineered to mimic the cellular functions, including erythrocytes, macrophages, leukocytes, tumor cells, and stem cells, etc [ 10 , [17] , [18] , [19] , [20] ]. Among them, erythrocytes membrane-coated nanocarriers have received much research attention for their long circulation half-life and low immunogenicity feature [ 21 ].…”

Low Doses of Resveratrol Protect Human Granulosa Cells from Induced-Oxidative Stress

“…Several pathways that lead to caspase activation, as well as to morphological and biochemical alterations in the cell, were observed [ 53 ]. Due to its function as a double-edged sword, mitochondrial-targeting research has been using RES to directly modulate the oxidative cell environment in different pathologies such as Alzheimer’s disease and within oncotherapies [ 54 , 55 , 56 ]. In this line, there is still a lack of studies regarding the role of RES in women with poor ART outcomes [ 54 ].…”

A Brief Updated Review of Advances to Enhance Resveratrol’s Bioavailability

“…Although organ targeted therapeutics is regarded as a major advancement, the boundaries have been pushed further to organelle targeted therapy. Following systemic administration of RES-loaded dual-modified novel biometric nanosystems, compounds cross the blood-brain barrier and target neuron cells, specifically by concentrating in the mitochondria [ 37 ]. These intravenously administered, neuronal mitochondria-targeted dual-modified novel biomimetic nanosystems may be potential therapeutic candidates for reactive oxygen species-induced mitochondrial dysfunction in Alzheimer’s disease [ 37 ].…”