Treatment Of Central Nervous System Diseases Research Articles

Brain delivery and activity of a lysosomal enzyme using a blood-brain barrier transport vehicle in mice.

Most lysosomal storage diseases (LSDs) involve progressive central nervous system (CNS) impairment, resulting from deficiency of a lysosomal enzyme. Treatment of neuronopathic LSDs remains a considerable challenge, as approved intravenously administered enzyme therapies are ineffective in modifying CNS disease because they do not effectively cross the blood-brain barrier (BBB). We describe a therapeutic platform for increasing the brain exposure of enzyme replacement therapies. The enzyme transport vehicle (ETV) is a lysosomal enzyme fused to an Fc domain that has been engineered to bind to the transferrin receptor, which facilitates receptor-mediated transcytosis across the BBB. We demonstrate that ETV fusions containing iduronate 2-sulfatase (ETV:IDS), the lysosomal enzyme deficient in mucopolysaccharidosis type II, exhibited high intrinsic activity and degraded accumulated substrates in both IDS-deficient cell and in vivo models. ETV substantially improved brain delivery of IDS in a preclinical model of disease, enabling enhanced cellular distribution to neurons, astrocytes, and microglia throughout the brain. Improved brain exposure for ETV:IDS translated to a reduction in accumulated substrates in these CNS cell types and peripheral tissues and resulted in a complete correction of downstream disease-relevant pathologies in the brain, including secondary accumulation of lysosomal lipids, perturbed gene expression, neuroinflammation, and neuroaxonal damage. These data highlight the therapeutic potential of the ETV platform for LSDs and provide preclinical proof of concept for TV-enabled therapeutics to treat CNS diseases more broadly.

Brain Angiogenesis Induced by Nonviral Gene Therapy with Potential Therapeutic Benefits for Central Nervous System Diseases.

Gene therapy employing nanocarriers represents a promising strategy to treat central nervous system (CNS) diseases, where brain microvasculature is frequently compromised. Vascular endothelial growth factor (VEGF) is a key angiogenic molecule; however, its in vivo administration to the CNS by nonviral gene therapy has not been conducted. Hence, we prepared and physicochemically characterized four cationic niosome formulations (1-4), which were combined with pVEGF-GFP to explore their capacity to transfer the VEGF gene to CNS cells and achieve angiogenesis in the brain. Experiments in primary neuronal cells showed successful and safe transfection with niosome 4, producing double levels of biologically active VEGF in comparison to the rest of the formulations. Intracortical administration of niosome 4 based nioplexes in mouse brain validated the ability of this nonviral vector to deliver the VEGF gene to CNS cells, inducing brain angiogenesis and emerging as a promising therapeutic approach for the treatment of CNS diseases.

Differentiation of Human Mesenchymal Stem Cells from Wharton's Jelly Towards Neural Stem Cells Using A Feasible and Repeatable Protocol.

The transplantation of neural stem cells (NSCs) capable of regenerating to the cells of the central nervous system (CNS) is a promising strategy in the treatment of CNS diseases and injury. As previous studies have highlighted mesenchymal stem cells (MSCs) as a source of NSCs, this study aimed to develop a feasible, efficient, and reproducible method for the neural induction of MSCs isolated from Wharton’s jelly (hWJ-MSCs). We induced neural differentiation in a monolayer culture using epidermal growth factor, basic fibroblast growth factor, N2, and B27 supplements. This resulted in a homogenous population of proliferating cells that expressed certain neural markers at both the protein and mRNA levels. Flow cytometry and immunocytochemistry confirmed the expression of neural markers: nestin, sex-determining region Y (SRY) box 1 and 2 (SOX1 and SOX2), microtubule-associated protein 2 (MAP2), and glial fibrillary acidic protein (GFAP). The qRT-PCR analysis revealed significantly enhanced expression of nestin and MAP2 in differentiated cells. This study confirms that it is possible to generate NSCs-like cells from hWJ-MSCs in a 2D culture using a practical method. However, the therapeutic effectiveness of such differentiated cells should be extended to confirm the terminal differentiation ability and electrophysiological properties of neurons derived from them.

Conversion of Benzimidazoles, Imidazothiazoles and Imidazoles into more Potent Central Nervous System Acting Drugs.

Benzimidazole (albendazole), imidazothiazole (levamisole) and imidazole (euconazole) are used in chemotherapy of helminthosis and mycosis respectively, with central nervous system (CNS) side effects. But only a limited number of azole groups are used clinically in the treatment of CNS diseases, which are on increase and could not be cured permanently. Due to increased incidence of more challenging new CNS diseases, there is a need for the synthesis of more potent CNS drugs. Hence, literature studies were carried out for the identification of common pathways for the synthesis of the three groups of compounds, their CNS properties and the possibility of modifying them to potent CNS drugs. Findings have shown that gloxal with formaldehyde in the presence of ammonia can be converted into imidazole, imidazothiazole and benzimidazole via distillation, condensation, alkylation, acylation, oxidation, cyclization, sulphation and amidation. However, agents such as phosphorus pentoxide, ethanolic potassium hydroxide, sodium hypochlorite, sodium hexafluroaluminate, aniline, calcium acetate, calcium benzoate, sodium hydroxide, aromatic aldehydes, bromoketones, alpha dicarbonyl compounds among others are used as reagents. The furan ring(s) may have a strong capability of penetrating CNS for the treatment of neurological disorders. The products from the three groups have agonistic, antagonistic, mixed agonistic and mixed antagonistic depressant and stimulant activities due to the presence of heteroatoms such as nitrogen, oxygen and sulphur. Imidazole may be the most potent with best characteristics of CNS penetrability and activity followed by imidazothiazole and benzimidazole. Azole group is common to all the three classes and may be responsible for some of their CNS effects. The resultant compounds could act via all neurotransmitters, voltage and ligand-gated ion channels and may be chiral.

Astrocyte and Oligodendrocyte Cross-Talk in the Central Nervous System.

Over the last decade knowledge of the role of astrocytes in central nervous system (CNS) neuroinflammatory diseases has changed dramatically. Rather than playing a merely passive role in response to damage it is clear that astrocytes actively maintain CNS homeostasis by influencing pH, ion and water balance, the plasticity of neurotransmitters and synapses, cerebral blood flow, and are important immune cells. During disease astrocytes become reactive and hypertrophic, a response that was long considered to be pathogenic. However, recent studies reveal that astrocytes also have a strong tissue regenerative role. Whilst most astrocyte research focuses on modulating neuronal function and synaptic transmission little is known about the cross-talk between astrocytes and oligodendrocytes, the myelinating cells of the CNS. This communication occurs via direct cell-cell contact as well as via secreted cytokines, chemokines, exosomes, and signalling molecules. Additionally, this cross-talk is important for glial development, triggering disease onset and progression, as well as stimulating regeneration and repair. Its critical role in homeostasis is most evident when this communication fails. Here, we review emerging evidence of astrocyte-oligodendrocyte communication in health and disease. Understanding the pathways involved in this cross-talk will reveal important insights into the pathogenesis and treatment of CNS diseases.

Multifunctional Polymeric Nanoplatforms for Brain Diseases Diagnosis, Therapy and Theranostics.

The blood–brain barrier (BBB) acts as a barrier to prevent the central nervous system (CNS) from damage by substances that originate from the blood circulation. The BBB limits drug penetration into the brain and is one of the major clinical obstacles to the treatment of CNS diseases. Nanotechnology-based delivery systems have been tested for overcoming this barrier and releasing related drugs into the brain matrix. In this review, nanoparticles (NPs) from simple to developed delivery systems are discussed for the delivery of a drug to the brain. This review particularly focuses on polymeric nanomaterials that have been used for CNS treatment. Polymeric NPs such as polylactide (PLA), poly (D, L-lactide-co-glycolide) (PLGA), poly (ε-caprolactone) (PCL), poly (alkyl cyanoacrylate) (PACA), human serum albumin (HSA), gelatin, and chitosan are discussed in detail.

Engineering mesenchymal stromal/stem cell-derived extracellular vesicles with improved targeting and therapeutic efficiency for the treatment of central nervous system disorders.

Engineering mesenchymal stromal/stem cell-derived extracellular vesicles with improved targeting and therapeutic efficiency for the treatment of central nervous system disorders.

Perivascular and Perineural Pathways Involved in Brain Delivery and Distribution of Drugs after Intranasal Administration.

One of the most challenging aspects of treating disorders of the central nervous system (CNS) is the efficient delivery of drugs to their targets within the brain. Only a small fraction of drugs is able to cross the blood–brain barrier (BBB) under physiological conditions, and this observation has prompted investigation into the routes of administration that may potentially bypass the BBB and deliver drugs directly to the CNS. One such route is the intranasal (IN) route. Increasing evidence has suggested that intranasally-administered drugs are able to bypass the BBB and access the brain through anatomical pathways connecting the nasal cavity to the CNS. Though the exact mechanisms regulating the delivery of therapeutics following IN administration are not fully understood, current evidence suggests that the perineural and perivascular spaces of the olfactory and trigeminal nerves are involved in brain delivery and cerebral perivascular spaces are involved in widespread brain distribution. Here, we review evidence for these delivery and distribution pathways, and we address questions that should be resolved in order to optimize the IN route of administration as a viable strategy to treat CNS disease states.

RARE-22. CHALLENGES IN MANAGEMENT OF CNS INVOLVEMENT OF CUTANEOUS T-CELL LYMPHOMA

Abstract BACKGROUND Cutaneous T-cell lymphoma (CTCL) is a group of T-cell lymphomas occurring primarily in the skin, without evidence of disease elsewhere. Central nervous system (CNS) involvement of CTCL is extremely rare, with a reported incidence of 5–9%. Due to its infrequency and radiographic appearance which mimics other CNS processes, CNS CTCL may be misdiagnosed. Here, we describe 8 cases of CNS CTCL at a single institution. METHODS The electronic medical records at our institution were queried for cases of CNS involvement by CTCL, between 2004–19. Clinical data, imaging and surgical pathology were reviewed. RESULTS Eight patients were diagnosed with CNS CTCL with median age of 68 and median time to development of CNS disease of 17 months. 1 patient had synchronous presentation of cutaneous and CNS disease identified at autopsy. Seven out of eight patients presented neurologically with behavioral and mental status changes and 1 patient had concurrent intraocular disease. Imaging showed bilateral non-enhancing T2/FLAIR signal changes in three patients; multifocal enhancement was noted in the others. Malignancy, inflammatory processes and infections including progressive multifocal leukoencephalopathy (PML) were often included in the radiographic differential diagnosis. Prior systemic therapies were variable, including palliative radiation, phototherapy, myeloablative chemotherapy followed by allogeneic stem cell transplant and oral methotrexate. 5 of 8 patients had active cutaneous disease at the time of CNS relapse. Six patients received initial treatment for CNS disease with high-dose methotrexate (HD-MTX). Comprehensive genomic analysis revealed recurrent alterations in genes associated with regulatory T-cell differentiation (SOCS1, NOTCH1), tumor suppressors (CDKN2A, PTEN, TP53); one case was hypermutated. CONCLUSIONS CNS involvement of CTCL is rare, occurring more than a year after initial cutaneous disease. Clinical and radiographic findings may be variable, necessitating high clinical suspicion. Most patients respond to HD-MTX. Further molecular analysis is ongoing.

Potential Regulation Mechanisms of P-gp in the Blood-Brain Barrier in Hypoxia.

The blood-brain barrier (BBB) is a barrier of the central nervous system (CNS), which can restrict the free exchange of substances, such as toxins and drugs, between cerebral interstitial fluid and blood, keeping the relative physiological stabilization. The brain capillary endothelial cells, one of the structures of the BBB, have a variety of ATP-binding cassette transporters (ABC transporters), among which the most widely investigated is Pglycoprotein (P-gp) that can efflux numerous substances out of the brain. The expression and activity of P-gp are regulated by various signal pathways, including tumor necrosis factor-α (TNF-α)/protein kinase C-β (PKC- β)/sphingosine-1-phosphate receptor 1 (S1P), vascular endothelial growth factor (VEGF)/Src kinase, etc. However, it remains unclear how hypoxic signaling pathways regulate the expression and activity of P-gp in brain microvascular endothelial cells. According to previous research, hypoxia affects the expression and activity of the transporter. If the transporter is up-regulated, some drugs enter the brain's endothelial cells and are pumped back into the blood by transporters such as P-gp before they enter the brain tissue, consequently influencing the drug delivery in CNS; if the transporter is down-regulated, the centrally toxic drug would enter the brain tissue and cause serious adverse reactions. Therefore, studying the mechanism of hypoxia-regulating P-gp can provide an important reference for the treatment of CNS diseases with a hypoxia/reoxygenation (H/R) component. This article summarized the mechanism of regulation of P-gp in BBB in normoxia and explored that of hypoxia.

Pleotropic Roles of Autotaxin in the Nervous System Present Opportunities for the Development of Novel Therapeutics for Neurological Diseases.

Autotaxin (ATX) is a soluble extracellular enzyme that is abundant in mammalian plasma and cerebrospinal fluid (CSF). It has two known enzymatic activities, acting as both a phosphodiesterase and a phospholipase. The majority of its biological effects have been associated with its ability to liberate lysophosphatidic acid (LPA) from its substrate, lysophosphatidylcholine (LPC). LPA has diverse pleiotropic effects in the central nervous system (CNS) and other tissues via the activation of a family of six cognate G protein-coupled receptors. These LPA receptors (LPARs) are expressed in some combination in all known cell types in the CNS where they mediate such fundamental cellular processes as proliferation, differentiation, migration, chronic inflammation, and cytoskeletal organization. As a result, dysregulation of LPA content may contribute to many CNS and PNS disorders such as chronic inflammatory or neuropathic pain, glioblastoma multiforme (GBM), hemorrhagic hydrocephalus, schizophrenia, multiple sclerosis, Alzheimer's disease, metabolic syndrome-induced brain damage, traumatic brain injury, hepatic encephalopathy-induced cerebral edema, macular edema, major depressive disorder, stress-induced psychiatric disorder, alcohol-induced brain damage, HIV-induced brain injury, pruritus, and peripheral nerve injury. ATX activity is now known to be the primary biological source of this bioactive signaling lipid, and as such, represents a potentially high-value drug target. There is currently one ATX inhibitor entering phase III clinical trials, with several additional preclinical compounds under investigation. This review discusses the physiological and pathological significance of the ATX-LPA-LPA receptor signaling axis and summarizes the evidence for targeting this pathway for the treatment of CNS diseases.

Research progress on adenosine in central nervous system diseases.

As an endogenous neuroprotectant agent, adenosine is extensively distributed and is particularly abundant in the central nervous system (CNS). Under physiological conditions, the concentration of adenosine is low intra‐ and extracellularly, but increases significantly in response to stress. The majority of adenosine functions are receptor‐mediated, and primarily include the A1, A2A, A2B, and A3 receptors (A1R, A2AR, A2BR, and A3R). Adenosine is currently widely used in the treatment of diseases of the CNS and the cardiovascular systems, and the mechanisms are related to the disease types, disease locations, and the adenosine receptors distribution in the CNS. For example, the main infarction sites of cerebral ischemia are cortex and striatum, which have high levels of A1 and A2A receptors. Cerebral ischemia is manifested with A1R decrease and A2AR increase, as well as reduction in the A1R‐mediated inhibitory processes and enhancement of the A2AR‐mediated excitatory process. Adenosine receptor dysfunction is also involved in the pathology of Alzheimer's disease (AD), depression, and epilepsy. Thus, the adenosine receptor balance theory is important for brain disease treatment. The concentration of adenosine can be increased by endogenous or exogenous pathways due to its short half‐life and high inactivation properties. Therefore, we will discuss the function of adenosine and its receptors, adenosine formation, and metabolism, and its role for the treatment of CNS diseases (such as cerebral ischemia, AD, depression, Parkinson's disease, epilepsy, and sleep disorders). This article will provide a scientific basis for the development of novel adenosine derivatives through adenosine structure modification, which will lead to experimental applications.

TGF-β Secretion by M2 Macrophages Induces Glial Scar Formation by Activating Astrocytes In Vitro.

Transforming growth factor-β (TGF-β) is a key factor that promotes fibrosis or scar formation, which could become an obstacle in the repair of impaired axons in the central nervous system (CNS) of the human body resulting from diseases or injuries. Considering that major pathological reactions occur during this process, we focused on TGF-secreting M2 macrophages to identify the interactions between M2 macrophages and astrocytes (AS) and verify the specific mechanism of fibrosis or glial scar formation. In the present study, we used the Transwell coculturing technique and found an increase in glial fibrillary acidic protein (GFAP), neurocan, IL-13, and TGF-β expression after incubation for 48h; the expression of these proteins decreased when additional inhibitors of the TGF-β receptor were added. We concluded that fibrosis or glial scar formation would be enhanced by the secretion of neurocan from AS, resulting from the release of TGF-β from M2 macrophages. We also used M2 macrophage-conditioned medium to further confirm this finding in a subsequent experiment. We hope that the findings in this research could provide a foundation for locating new targets for treating CNS diseases or injuries.

MiR‑29 promotes the proliferation of cultured rat neural stem/progenitor cells via the PTEN/AKT signaling pathway.

Neural stem/progenitor cells (NSPCs) are self-renewing, multipotent cells and remain in the human brain throughout an individual's lifetime. NSPCs are activated by brain damage and contribute towards repair and motor function recovery in the central nervous system (CNS). It was previously reported that miR-29 was involved in regulating proliferation, differentiation and survival in hepatocellular carcinoma, and osteoblast and mantle cell lymphoma; however, the effects of miR-29 on NSPCs remain unclear. In the present study, it was demonstrated via Cell Counting Kit-8 assays that overexpression of miR-29 promoted the viability of NPSCs, and downregulated the expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) protein. Additionally, treatment with a PTEN-specific inhibitor (VO-OHpic trihydrate) abolished the effects of the miR-29 inhibitor on PTEN expression, as determined via western blotting. Flow cytometry and 5-bromo-2-deoxyuridine (BrdU) staining revealed that overexpression of miR-29 further promoted the proliferation of NSPCs; however, knocking down miR-29 inhibited cell proliferation. VO-OHpic trihydrate reversed the effects of miR-29 knockdown on cell proliferation. Furthermore, it was observed that overexpression of miR-29 increased the phosphorylation levels of AKT. Collectively, the results indicated that overexpression of miR-29 promoted the proliferation of cultured rat NSPCs and decreased the expression of PTEN protein, and that the activation of Akt may be a potential underlying mechanism. The present findings may provide novel insight for the development of strategies for stem cell-mediated treatment of CNS diseases.

Neuroprotective Effects of Anthraquinones from Rhubarb in Central Nervous System Diseases.

Rhubarb is a well-known traditional Chinese medicine; it has been used in China for thousands of years. Rhubarb anthraquinones are the major medicinal ingredients derived from rhubarb including emodin, aloe-emodin, chrysophanol, rhein, physcion, and danthron. These different anthraquinone derivatives alone or in combination play a therapeutic role in central nervous system diseases (CNSD), such as cerebral ischemic stroke, intracerebral hemorrhage, traumatic brain injury, brain tumor, Alzheimer's disease, depression, and others. We review the experimental studies on these six anthraquinones in the treatment of CNSD by consulting literature published in the last 20 years in PubMed and then give a future perspective on it. In the end of this paper some deficiencies related to these studies also have been pointed out.

Application of Virus Targeting Nanocarrier Drug Delivery System in Virus-Induced Central Nervous System Disease Treatment.

Virus-induced central nervous system (CNS) diseases represent a significant burden to animal health worldwide. The difficulty in treating these diseases is mainly attributable to the elaborate barrier system, which limits the transport of drugs to the infected sites. Therefore, it is necessary to develop smart delivery technologies for treatment of these diseases. In the study, viral nervous necrosis disease was studied as a model to evaluate the feasibility of multiwalled carbon nanotubes (MWCNTs) conjugated with virus-specific nanobody and antiviral drug for targeted therapy of virus-induced CNS diseases. The virus (named as PGNNV) was isolated, identified and purified from diseased grouper. A naïve phage-displayed alpaca nanobody library was constructed, and the purified PGNNV was used for biopanning of PGNNV-specific nanobody from the library. The targeted delivery system based on MWCNTs conjugated with polyethylenimine, ribavirin, and PGNNV-specific nanobody was constructed and designated as MWCNTs-PEI-R-Nb. Targeting ability and treatment effects of the MWCNTs-PEI-R-Nb were checked both in vitro and in vivo. MWCNTs-PEI-R-Nb showed an increasing distribution in PGNNV-infected cells, and an obvious accumulation in the brain of PGNNV-infected zebrafish larvae. MWCNTs-PEI-R-Nb also showed a strong anti-PGNNV ability both in vitro and in vivo. The mortality of larvae treated with MWCNTs-PEI-R-Nb (equivalent to 100 mg/L ribavirin) was 27% during 10 days post infection, whereas it was 100% for the control group. The results so far indicate that MWCNTs conjugated with antiviral drugs and viral-specific antibody are effective means for virus-induced CNS disease targeted therapy.

Focused ultrasound-induced blood brain-barrier opening enhanced vascular permeability for GDNF delivery in Huntington's disease mouse model

BackgroundHuntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the gene encoding the huntingtin (Htt) protein, which results in a protein containing an abnormally expanded polyglutamine (polyQ) sequence. The expanded polyQ in the Htt protein is toxic to brain cells. No therapy exists to delay disease progression. MethodsThis study describes a gene-liposome system that synergistically applied focused ultrasound (FUS)-blood-brain barrier (BBB) opening for rescuing motor and neuropathological impairments when administered from pre to post-symptomatic transgenic mouse models of HD. DPPC liposomes (LPs) are designed to carry glia cell line-derived neurotrophic factor (GDNF) plasmid DNA (GDNFp) to form a GDNFp-liposome (GDNFp-LPs) complex. Pulsed FUS exposure with microbubbles (MBs) was used to induce BBB opening for non-viral, non-invasive, and targeted gene delivery into the central nervous system (CNS) for therapeutic purposes. ResultsFUS-gene therapy significantly improved motor performance with GDNFp-LPs + FUS treated HD mice equilibrating longer periods in the animal behavior. Reflecting the improvements observed in motor function, GDNF overexpression results in significantly decreased formation of polyglutamine-expanded aggregates, reduced oxidative stress and apoptosis, promoted neurite outgrowth, and improved neuronal survival. Immunoblotting and histological staining further confirmed the neuroprotective effect from delivery of GDNF genes to neuronal cells. ConclusionsThis study suggests that the GDNFp-LPs plus FUS sonication can provide an effective gene therapy to achieve local extravasation and triggered gene delivery for non-invasive in vivo treatment of CNS diseases.

Single-Domain Antibodies as Therapeutic and Imaging Agents for the Treatment of CNS Diseases.

Antibodies have become one of the most successful therapeutics for a number of oncology and inflammatory diseases. So far, central nervous system (CNS) indications have missed out on the antibody revolution, while they remain ‘hidden’ behind several hard to breach barriers. Among the various antibody modalities, single-domain antibodies (sdAbs) may hold the ‘key’ to unlocking the access of antibody therapies to CNS diseases. The unique structural features of sdAbs make them the smallest monomeric antibody fragments suitable for molecular targeting. These features are of particular importance when developing antibodies as modular building blocks for engineering CNS-targeting therapeutics and imaging agents. In this review, we first introduce the characteristic properties of sdAbs compared to traditional antibodies. We then present recent advances in the development of sdAbs as potential therapeutics across brain barriers, including their use for the delivery of biologics across the blood–brain and blood–cerebrospinal fluid (CSF) barriers, treatment of neurodegenerative diseases and molecular imaging of brain targets.

Cannabidiol Enhances the Passage of Lipid Nanocapsules across the Blood-Brain Barrier Both in Vitro and in Vivo.

Diseases affecting the central nervous system (CNS) should be regarded as a major health challenge due to the current lack of effective treatments given the hindrance to brain drug delivery imposed by the blood-brain barrier (BBB). Since efficient brain drug delivery should not solely rely on passive targeting, active targeting of nanomedicines into the CNS is being explored. The present study is devoted to the development of lipid nanocapsules (LNCs) decorated with nonpsychotropic cannabinoids as pioneering nonimmunogenic brain-targeting molecules and to the evaluation of their brain-targeting ability both in vitro and in vivo. Noticeably, both the permeability experiments across the hCMEC/D3 cell-based in vitro BBB model and the biodistribution experiments in mice consistently demonstrated that the highest brain-targeting ability was achieved with the smallest-sized cannabinoid-decorated LNCs. Importantly, the enhancement in brain targeting achieved with the conjugation of cannabidiol to LNCs outperformed by 6-fold the enhancement observed for the G-Technology (the main brain active strategy that has already entered clinical trials for the treatment of CNS diseases). As the transport efficiency across the BBB certainly determines the efficacy of the treatments for brain disorders, small cannabinoid-decorated LNCs represent auspicious platforms for the design and development of novel therapies for CNS diseases.

A Bioinspired Platform for Effective Delivery of Protein Therapeutics to the Central Nervous System.

Central nervous system (CNS) diseases are the leading cause of morbidity and mortality; their treatment, however, remains constrained by the blood-brain barrier (BBB) that impedes the access of most therapeutics to the brain. A CNS delivery platform for protein therapeutics, which is achieved by encapsulating the proteins within nanocapsules that contain choline and acetylcholine analogues, is reported herein. Mediated by nicotinic acetylcholine receptors and choline transporters, such nanocapsules can effectively penetrate the BBB and deliver the therapeutics to the CNS, as demonstrated in mice and non-human primates. This universal platform, in general, enables the delivery of any protein therapeutics of interest to the brain, opening a new avenue for the treatment of CNS diseases.