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The blood-brain barrier (BBB) is a special structure in the central nervous system (CNS), whose delicate properties can protect the brain from the attack by harmful large molecules and organisms within blood circulation. However, the very barrier also prevents the brain-targeted drugs from taking effects, posing great challenge to the treatment of neurodegenerative diseases, glioma and other brain diseases. With the development of nanotechnology, more and more nanoparticles (NPs) have been developed as drug carriers, which can facilitate the drug with various mechanisms to get across the BBB. This article starts with introduction of the BBB, explaining the complexity of BBB structure and its unique features to form barriers, so that we can understand the difficulty in transporting drug into the BBB and the potential methods of targeting and permeate the barrier. Next, we focus on three main types of NPs that have been applied in the brain-targeted drug delivery system: polymeric-based NPs; biomimetic-based NPs and inorganic-based NPs. Furthermore, we deal with the specific NPs drug delivery strategies, which include absorption-mediated, carrier-mediated and receptor-mediated transcytosis. At the end of the article, we talk about the leading trend and future development of the brain-targeted nanoparticle drug delivery systems.

As a neurological disorder in the brain, epilepsy is not only associated with abnormal synchronized discharging of neurons, but also inseparable from non-neuronal elements in the altered microenvironment. Anti-epileptic drugs (AEDs) merely focusing on neuronal circuits frequently turn out deficient, which is necessitating comprehensive strategies of medications to cover over-exciting neurons, activated glial cells, oxidative stress and chronic inflammation synchronously. Therefore, we would report the design of a polymeric micelle drug delivery system that was functioned with brain targeting and cerebral microenvironment modulation. In brief, reactive oxygen species (ROS)-sensitive phenylboronic ester was conjugated with poly-ethylene glycol (PEG) to form amphiphilic copolymers. Additionally, dehydroascorbic acid (DHAA), an analogue of glucose, was applied to target glucose transporter 1 (GLUT1) and facilitate micelle penetration across the blood‒brain barrier (BBB). A classic hydrophobic AED, lamotrigine (LTG), was encapsulated in the micelles via self-assembly. When administrated and transferred across the BBB, ROS-scavenging polymers were expected to integrate anti-oxidation, anti-inflammation and neuro-electric modulation into one strategy. Moreover, micelles would alter LTG distribution in vivo with improved efficacy. Overall, the combined anti-epileptic therapy might provide effective opinions on how to maximize neuroprotection during early epileptogenesis. The micelles manage to cross the blood–brain barrier and then degrade under reactive oxygen species stimulation to release lamotrigine for anti-epileptic neuroprotection and glial stabilization. [Display omitted] [ABSTRACT FROM AUTHOR]

Brain diseases, including neurodegenerative diseases, acute ischemic stroke and brain tumors, have become a major health problem and a huge burden on society with high morbidity and mortality. However, most of the current therapeutic drugs can only relieve the symptoms of brain diseases, and it is difficult to achieve satisfactory therapeutic effects fundamentally. Extensive studies have shown that the therapeutic effects of brain diseases are mainly affected by two factors: the conservation of the blood–brain barrier (BBB) and the complexity of the brain micro‐environment. Brain‐targeting drug delivery systems provide new possibilities for overcoming these barriers with versatility. In this review, it provides an overview of BBB alteration and discusses targeting delivery strategies for brain diseases therapy. Furthermore, delivery systems which are designed to modulate the brain micro‐environment with synergistic effects were also highlighted. This article is categorized under:Therapeutic Approaches and Drug Discovery > Emerging Technologies [ABSTRACT FROM AUTHOR]

Blood–brain barrier (BBB) strictly controls matter exchange between blood and brain, and severely limits brain penetration of systemically administered drugs, resulting in ineffective drug therapy of brain diseases. However, during the onset and progression of brain diseases, BBB alterations evolve inevitably. In this review, we focus on nanoscale brain-targeting drug delivery strategies designed based on BBB evolutions and related applications in various brain diseases including Alzheimer's disease, Parkinson's disease, epilepsy, stroke, traumatic brain injury and brain tumor. The advances on optimization of small molecules for BBB crossing and non-systemic administration routes (e. g., intranasal treatment) for BBB bypassing are not included in this review. Blood–brain barrier (BBB) is evolving during the onset and progression of brain diseases. BBB evolution-based nanoscale brain-targeting drug delivery strategies are summarized in this review for various brain diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

Metabolic microenvironment dysfunction remains hallmarks of acute ischemic stroke (AIS) throughout the ischemia, reperfusion, and recovery stages. Existing therapeutic strategies focus only on a single pathological process, while cascading metabolic changes are neglected. For the sake of better long-term prognosis, interventions in each stage are certainly worthwhile if achievable. Herein, inspired by the natural hemoglobin (Hb) carrying oxygen mechanism, a polymer-based nanoerythrocyte is designed to remodel the metabolic microenvironment in the whole stages of AIS. Briefly, Hb and methoxatin are incorporated into polydopamine nanocage which is further coated with the polymer layer formed by in-situ free radical polymerization. Modified with microthrombus-targeting peptide, this nanoerythrocyte can actively accumulate in the ischemic core and respond to the metabolic microenvironment. In vivo results demonstrate that cellular metabolic homeostasis and responsiveness are restored by oxygen balance regulation, microglia polarization, glucose metabolism activation, and neovascularization in permanent and transient middle cerebral artery occlusion model mice. The behavioral experiment results also confirm the effects of nanoerythrocyte for long-term prognosis. This strategy gives a proof of concept that metabolic microenvironment modulation is a promising perspective for AIS treatment with nanoerythrocytes. [Display omitted] • Microthrombus-targeted nanoerythrocyte penetrates the damaged blood-brain barrier and reaches the ischemic core. • Nanoerythrocyte responds to the level of oxygen and reactive oxygen species during different stages of acute ischemic stroke. • A multi-cellular metabolic modulation strategy is beneficial for the long-term prognosis of acute ischemic stroke. [ABSTRACT FROM AUTHOR]

Tumor metastasis is a significant contributor to the mortality of cancer patients. Specifically, current conventional treatments are unable to achieve complete remission of brain metastasis. This is due to the unique pathological environment of brain metastasis, which differs significantly from peripheral metastasis. Brain metastasis is characterized by high tumor mutation rates and a complex microenvironment with immunosuppression. Additionally, the presence of blood-brain barrier (BBB)/blood tumor barrier (BTB) restricts drug leakage into the brain. Therefore, it is crucial to take account of the specific characteristics of brain metastasis when developing new therapeutic strategies. Nanomaterials offer promising opportunities for targeted therapies in treating brain metastasis. They can be tailored and customized based on specific pathological features and incorporate various treatment approaches, which makes them advantageous in advancing therapeutic strategies for brain metastasis. This review provides an overview of current clinical treatment options for patients with brain metastasis. It also explores the roles and changes that different cells within the complex microenvironment play during tumor spread. Furthermore, it highlights the use of nanomaterials in current brain treatment approaches. [Display omitted] • The unique pathological environment of brain metastases limits clinical outcomes. • Different cell types play different roles and change during the progression of BM. • NMs can be customized to specific pathological features and thus offer significant advantages in BM treatment. [ABSTRACT FROM AUTHOR]