Synaptic vesicle-inspired nanoparticles with spatiotemporally controlled release ability as a "nanoguard" for synergistic treatment of synucleinopathies.

Synaptic vesicle-inspired nanoparticles (RT-PPB NPs) as a "nanoguard" were designed for clearing the toxic α-synuclein aggregates in diseased neurons and preventing the culprits from escaping to affect other normal cells. The NPs could overcome a series of tissue and cellular barriers and controllably release drugs in the diseased neurons, which ensured the optimization of synergistic treatment. This study indicates that the synaptic vesicle-inspired NPs may have the potential to open up a new avenue for the treatment of synucleinopathies, as well as other neurodegenerative diseases.

Traceable Nano-Biohybrid Complexes by One-Step Synthesis as CRISPR-Chem Vectors for Neurodegenerative Diseases Synergistic Treatment.

Abnormal protein aggregations are essential pathological features of neurodegenerative diseases. Eliminating while inhibiting the regeneration of these protein aggregates is considered an effective treatment strategy. Herein, the CRISPR/Cas9 gene-editing tool is employed to inhibit the regeneration of disease-related proteins, while chemical drugs are applied to eliminate the proteins that are produced. To efficiently deliver CRISPR-chem drugs into brain lesions, traceable nano-biohybrid complexes (F-TBIO) are constructed by one-step synthesis and CRISPR/Cas9 plasmids (CF-TBIO) are loaded in a controllable manner. CF-TBIO can knock out the BACE1 gene and reduce the burden of amyloid-ß, and thereby significantly improve the cognitive abilities of 2xTg-AD mice. In particular, by prolonging the dosing interval, the pathological damage and behavioral abilities of 2xTg-AD mice are still significantly improved. During the therapeutic process, CF-TBIO with a high relaxation rate provides accurate imaging signals in the complex brain physiological environment. The finding shows that CF-TBIO has great potential to serve as a CRISPR-chem drug-delivery platform for neurodegenerative diseases therapy.

Targeted exosome coating gene-chem nanocomplex as "nanoscavenger" for clearing α-synuclein and immune activation of Parkinson's disease.

The most critical problem in the treatment of neurodegenerative diseases is brain neuronal protection, which can be overcome by clearing pathological substances and regulating the immune environment. In the above treatment strategies, the traditional poor drug delivery problem is inevitable. Here, we show an engineering core-shell hybrid system named rabies virus glycoprotein (RVG) peptide-modified exosome (EXO) curcumin/phenylboronic acid-poly(2-(dimethylamino)ethyl acrylate) nanoparticle/small interfering RNA targeting SNCA (REXO-C/ANP/S). It is a nanoscavenger for clearing α-synuclein aggregates and reducing their cytotoxicity in Parkinson's disease neurons. The motor behavior of Parkinson's disease mice is substantially improved after REXO-C/ANP/S treatment. In particular, we demonstrate that REXO-C/ANP/S is also a nanoscavenger for clearing immune activation due to its natural immature dendritic cell EXO coating. Our findings show that REXO-C/ANP/S may serve as a platform for neurodegenerative diseases treatment.

A Reactive Oxygen Species-Responsive Poly(amino acids) Nanoparticle Loading Doxorubicin for Glioblastoma Multiforme Treatment.

Amino acids are significant for human life and therefore considered as the crucial nutrients for human body with high biosafety. Due to their high biocompatibilities and various physicochemical properties, their polymers can be applied to construct drug delivery systems for various diseases' treatments. Among them, glioblastoma multiforme received special attention and numerous efforts regarding to nanotechnology were developed to treat such tumor. However, the biosafety of the delivering materials in those efforts arises as a critical issue in consideration of the weak patients. Therefore, a ROSresponsive nanoparticle (DOX@PLSPL) with poly(amino acids) encapsulating doxorubicin was developed for glioblastoma multiforme treatment. DOX@PLSPL was constructed by poly-lysine and poly-leucine with high biocompatibility. The high doxorubicin encapsulation efficiency and the controlled release manner of DOX@PLSPL ensured its high anti-tumor effect. Totally, this DOX@PLSPL can be used as a promising drug delivery system for glioblastoma multiforme treatments.

Combined-therapeutic strategies synergistically potentiate glioblastoma multiforme treatment via nanotechnology.

Glioblastoma multiforme (GBM) is a highly aggressive and devastating brain tumor characterized by poor prognosis and high rates of recurrence. Numerous therapeutic strategies and delivery systems are developed to prolong the survival time. They exhibit enhanced therapeutic effects in animal models, whereas few of them is applied in clinical trials. Taking into account the drug-resistance and high recurrence of GBM, combined-therapeutic strategies are exploited to maximize therapeutic efficacy. The combined therapies demonstrate superior results than those of single therapies against GBM. The co-therapeutic agents, the timing of therapeutic strategies and the delivery systems greatly affect the overall outcomes. Herein, the current advances in combined therapies for glioblastoma via systemic administration are exhibited in this review. And we will discuss the pros and cons of these combined-therapeutic strategies via nanotechnology, and provide the guidance for developing rational delivery systems to optimize treatments against GBM and other malignancies in central nervous system.

An "Amyloid-ß Cleaner" for the Treatment of Alzheimer's Disease by Normalizing Microglial Dysfunction.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by progressive cognitive and memory loss. The vicious circle between dysfunctional microglia and amyloid-ß (Aß) is a crucial pathological event and accelerates the progression of AD. Herein, a zwitterionic poly(carboxybetaine) (PCB)-based nanoparticle (MCPZFS NP) with normalizing the dysfunctional microglia and Aß recruitment is established for the treatment of AD. Compared with the neural polyethylene glycol (PEG)-based nanoparticles (MEPZFS NPs), the MCPZFS NPs significantly alleviate the priming of microglia by decreasing the level of proinflammatory mediators and promoting the secretion of BDNF. Most importantly, quite different from PEG, the PCB-based NPs exhibit the behavior to recruit Aß into microglia, which significantly enhances the Aß phagocytosis. Moreover, the Aß degradation is changed from the conventional lysosomal/autophagy to the proteasomal pathway in the presence of MCPZFS NPs. After the treatment with MCPZFS NPs, the Aß burden, neuron damages, memory deficits, and neuroinflammation of APPswe/PS1dE9 mice are significantly attenuated in the brain. Therefore, the PCB-based MCPZFS NPs have great potential to serve as an "Aß cleaner" and provide a new insight into the therapeutic strategy for AD therapy.