Neuronal mitochondrial dysfunction caused by excessive reactive oxygen species (ROS) is an early event of sporadic Alzheimer's disease (AD), and considered to be a key pathologic factor in the progression of AD. The targeted delivery of the antioxidants to mitochondria of injured neurons in brain is a promising therapeutic strategy for AD. A safe and effective drug delivery system (DDS) which is able to cross the blood-brain barrier (BBB) and target neuronal mitochondria is necessary. Recently, bioactive materials-based DDS has been widely investigated for the treatment of AD. Herein, we developed macrophage (MA) membrane-coated solid lipid nanoparticles (SLNs) by attaching rabies virus glycoprotein (RVG29) and triphenylphosphine cation (TPP) molecules to the surface of MA membrane (RVG/TPP-MASLNs) for functional antioxidant delivery to neuronal mitochondria. According to the results, MA membranes camouflaged the SLNs from being eliminated by RES-rich organs by inheriting the immunological characteristics of macrophages. The unique properties of the DDS after decoration with RVG29 on the surface was demonstrated by the ability to cross the BBB and the selective targeting to neurons. After entering the neurons in CNS, TPP further lead the DDS to mitochondria driven by electric charge. The Genistein (GS)- encapsulated DDS (RVG/TPP-MASLNs-GS) exhibited the most favorable effects on reliveing AD symptoms in vitro and in vivo by the synergies gained from the combination of MA membranes, RVG29 and TPP. These results demonstrated a promising therapeutic candidate for delaying the progression of AD via neuronal mitochondria-targeted delivery by the designed biomimetic nanosystems.

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 amyloid-β (Aβ) 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 Aβ-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.

Gene therapy aims to add, replace or turn off genes to help treat disease. To date, the US Food and Drug Administration (FDA) has approved 14 gene therapy products. With the increasing interest in gene therapy, feasible gene delivery vectors are necessary for inserting new genes into cells. There are different kinds of gene delivery vectors including viral vectors like lentivirus, adenovirus, retrovirus, adeno-associated virus et al, and non-viral vectors like naked DNA, lipid vectors, polymer nanoparticles, exosomes et al, with viruses being the most commonly used. Among them, the most concerned vector is adeno-associated virus (AAV) because of its safety, natural ability to efficiently deliver gene into cells and sustained transgene expression in multiple tissues. In addition, the AAV genome can be engineered to generate recombinant AAV (rAAV) containing transgene sequences of interest and has been proven to be a safe gene vector. Recently, rAAV vectors have been approved for the treatment of various rare diseases. Despite these approvals, some major limitations of rAAV remain, namely nonspecific tissue targeting and host immune response. Additional problems include neutralizing antibodies that block transgene delivery, a finite transgene packaging capacity, high viral titer used for per dose and high cost. To deal with these challenges, several techniques have been developed. Based on differences in engineering methods, this review proposes three strategies: gene engineering-based capsid modification (capsid modification), capsid surface tethering through chemical conjugation (surface tethering), and other formulations loaded with AAV (virus load). In addition, the major advantages and limitations encountered in rAAV engineering strategies are summarized.

Multi-level studies have shown that Rhodiola rosea (RHO) and Caffeine (CAF) have the potential to be nutritional supplements to enhance physical performance in resistance exercise-untrained and -trained subjects. This study examined the synergistic effects of RHO (262.7 mg/kg for rats and 2.4 g for volunteers) and CAF (19.7 mg/kg for rats and 3 mg/kg for volunteers) supplementation on improving physical performance in rats, resistance exercise-untrained volunteers and resistance exercise-trained volunteers. Rats and volunteers were randomly grouped into placebo, CAF, RHO and CAF+RHO and administered accordingly with the nutrients during the training procedure, and pre- and post-measures were collected. We found that RHO+CAF was effective in improving forelimb grip strength (13.75%), erythropoietin (23.85%), dopamine (12.65%) and oxygen consumption rate (9.29%) in the rat model. Furthermore, the current results also indicated that the combination of RHO+CAF significantly increased the bench press one-repetition maximum (1RM) (16.59%), deep squat 1RM (15.75%), maximum voluntary isometric contraction (MVIC) (14.72%) and maximum repetitions of 60% 1RM bench press (22.15%) in resistance exercise-untrained volunteers. Additionally, despite the excellent base level of the resistance exercise-trained volunteers, their deep squat 1RM and MVIC increased substantially through the synergistic effect of RHO and CAF. In conclusion, combined supplementation of RHO+CAF is more beneficial in improving the resistance exercise performance for both resistance exercise-untrained and -trained volunteers. The present results provide practical evidence that the synergies of RHO and CAF could serve as potential supplementary for individuals, especially resistance exercise-trained subjects, to ameliorate their physical performances effectively and safely.