Blood-brain barrier (BBB) is a natural protective membrane that prevents central nervous system (CNS) from toxins and pathogens in blood. However, the presence of BBB complicates the pharmacotherapy for CNS disorders as the most chemical drugs and biopharmaceuticals have been impeded to enter the brain. Insufficient drug delivery into the brain leads to low therapeutic efficacy as well as aggravated side effects due to the accumulation in other organs and tissues. Recent breakthrough in materials science and nanotechnology provides a library of advanced materials with customized structure and property serving as a powerful toolkit for targeted drug delivery. In-depth research in the field of anatomical and pathological study on brain and BBB further facilitates the development of brain-targeted strategies for enhanced BBB crossing. In this review, the physiological structure and different cells contributing to this barrier are summarized. Various emerging strategies for permeability regulation and BBB crossing including passive transcytosis, intranasal administration, ligands conjugation, membrane coating, stimuli-triggered BBB disruption, and other strategies to overcome BBB obstacle are highlighted. Versatile drug delivery systems ranging from organic, inorganic, and biologics-derived materials with their synthesis procedures and unique physio-chemical properties are summarized and analyzed. This review aims to provide an up-to-date and comprehensive guideline for researchers in diverse fields, offering perspectives on further development of brain-targeted drug delivery system. 

/pdf/the-blood-brain-barrier-structure-regulation-and-drug-17xefdia.pdf

The blood–brain barrier: structure, regulation, and drug delivery

Immune determinants of the pre-metastatic niche.

Recent advances in biomimetic nanodelivery systems: New brain-targeting strategies.

The limited benefits of immunotherapy against glioblastoma (GBM) is closely related to the paucity of T cells in brain tumor bed. Both systemic and local immunosuppression contribute to the deficiency of tumor-infiltrating T cells. However, the current studies focus heavily on the local immunosuppressive tumor microenvironment but not on the co-existence of systemic immunosuppression. Here, we develop a nanostructure named Nano-reshaper to co-encapsulate lymphopenia alleviating agent cannabidiol and lymphocyte recruiting cytokine LIGHT. The results show that Nano-reshaper increases the number of systemic T cells and improves local T-cell recruitment condition, thus greatly increasing T-cell infiltration. When combined with immune checkpoint inhibitor, this therapeutic modality achieves 83.3% long-term survivors without recurrence in GBM models in male mice. Collectively, this work unveils that simultaneous reprogramming of systemic and local immune function is critical for T-cell based immunotherapy and provides a clinically translatable option for combating brain tumors. 

https://www.nature.com/articles/s41467-023-35957-8.pdf

Reprogramming systemic and local immune function to empower immunotherapy against glioblastoma

Ischemic stroke (IS) constitutes the leading cause of global morbidity and mortality. Neuroprotectants are essential to ameliorate the clinical prognosis, but their therapeutic outcomes are tremendously compromised by insufficient delivery to the ischemic lesion and intricate pathogenesis associated with neuronal damage, oxidative stress, inflammation responses, blood-brain barrier (BBB) dysfunction, etc. Herein, a biomimetic nanosystem (Leo@NM-Lipo) composed of neutrophil membrane-fused nanoliposomal leonurine (Leo) is constructed, which can not only efficiently penetrate and repair the disrupted BBB but also robustly remodel the harsh cerebral microenvironment to reverse ischemia-reperfusion (I/R) injury. More specifically, the neutrophil membrane inherits the BBB penetrating, infarct core targeting, inflammation neutralization, and immune evasion properties of neutrophils, while Leo, a naturally occurring neuroprotectant, exerts pleiotropic effects to attenuate brain damage. Remarkably, comprehensive investigations disclose the critical factors influencing the targetability and therapeutic performances of biomimetic nanosystems. Leo@NM-Lipo with a low membrane protein-to-lipid ratio of 1:10 efficiently targets the ischemic lesion and rescues the injured brain by alleviating neuronal apoptosis, oxidative stress, neuroinflammation, and restoring BBB integrity in transient middle cerebral artery occlusion (tMCAO) rats. Taken together, our study provides a neutrophil-mimetic nanoplatform for targeted IS therapy and sheds light on the rational design of biomimetic nanosystems favoring wide medical applications. 

https://doi.org/10.1016/j.mtbio.2023.100674

Neutrophil membrane fusogenic nanoliposomal leonurine for targeted ischemic stroke therapy via remodeling cerebral niche and restoring blood-brain barrier integrity

Failure of conventional clinical therapies such as tumor resection and chemotherapy are mainly due to the ineffective control of tumor metastasis. Metastasis consists of three steps: (i) tumor cells extravasate from the primary sites into the circulation system via epithelial-mesenchymal transition (EMT), (ii) the circulating tumor cells (CTCs) form "micro-thrombi" with platelets to evade the immune surveillance in circulation, and (iii) the CTCs colonize in the pre-metastatic niche. Here, we design a systemic metastasis-targeted nanotherapeutic (H@CaPP) composed of an anti-inflammatory agent, piceatannol, and an anti-thrombotic agent, low molecular weight heparin, to hinder the multiple steps of tumor metastasis. H@CaPP is found efficiently impeded EMT, inhibited the formation of "micro-thrombi", and prevented the development of pre-metastatic niche. When combined with surgical resection or chemotherapy, H@CaPP efficiently inhibits tumor metastasis and prolonged overall survival of tumor-bearing mice. Collectively, we provide a simple and effective systemic metastasis-targeted nanotherapeutic for combating tumor metastasis.

/pdf/systemic-metastasis-targeted-nanotherapeutic-reinforces-4s08vikkiv.pdf

Systemic metastasis-targeted nanotherapeutic reinforces tumor surgical resection and chemotherapy.

High level of detrimental factors including reactive oxygen species (ROS) and inflammatory cytokines accumulated in the infarct core and their erosion to salvageable penumbra are key pathological cascades of ischemia-reperfusion injury in stroke. Few neuroprotectants can remodel the hostile microenvironment of the infarct core for the failure to interfere with dead or biofunctionally inactive dying cells. Even ischemia-reperfusion injury is temporarily attenuated in the penumbra by medications; insults of detrimental factors from the core still erode the penumbra continuously along with drug metabolism and clearance. Herein, a strategy named "nanobuffer" is proposed to neutralize detrimental factors and buffer destructive erosion to the penumbra. Inspired by neutrophils' tropism to the infarct core and affinity to inflammatory cytokines, poly(lactic-co-glycolic acid) (PLGA) nanoparticles are coated with neutrophil membrane to target the infarct core and absorb inflammatory cytokines; α-lipoic acid is decorated on the surface and cannabidiol is loaded for ROS scavenging and neuroprotection, respectively, to construct the basic unit of the nanobuffer. Such a nanobuffer exerts a comprehensive effect on the infarct area via detrimental factor neutralization and cannabidiol-induced neuroprotection. Besides, the nanobuffer can possibly be enhanced by dynamic ROP (ring-opening-polymerization)-induced membrane cross-fusion among closely adjacent units in vivo. Systematic evaluations show significant decrease of detrimental factors in the core and the penumbra, reduced infarct volume, and improved neurological recovery compared to the untreated group of stroke rats.

Neutrophil-Biomimetic "Nanobuffer" for Remodeling the Microenvironment in the Infarct Core and Protecting Neurons in the Penumbra via Neutralization of Detrimental Factors to Treat Ischemic Stroke.

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Systemic metastasis-targeted nanotherapeutic reinforces tumor surgical resection and chemotherapy.

Neutrophil-Biomimetic "Nanobuffer" for Remodeling the Microenvironment in the Infarct Core and Protecting Neurons in the Penumbra via Neutralization of Detrimental Factors to Treat Ischemic Stroke.