Compartmentalized ocular lymphatic system mediates eye-brain immunity.

The eye, an anatomical extension of the central nervous system (CNS), exhibits many molecular and cellular parallels to the brain. Emerging research demonstrates that changes in the brain are often reflected in the eye, particularly in the retina1. Still, the possibility of an immunological nexus between the posterior eye and the rest of the CNS tissues remains unexplored. Here, studying immune responses to herpes simplex virus in the brain, we observed that intravitreal immunization protects mice against intracranial viral challenge. This protection extended to bacteria and even tumours, allowing therapeutic immune responses against glioblastoma through intravitreal immunization. We further show that the anterior and posterior compartments of the eye have distinct lymphatic drainage systems, with the latter draining to the deep cervical lymph nodes through lymphatic vasculature in the optic nerve sheath. This posterior lymphatic drainage, like that of meningeal lymphatics, could be modulated by the lymphatic stimulator VEGFC. Conversely, we show that inhibition of lymphatic signalling on the optic nerve could overcome a major limitation in gene therapy by diminishing the immune response to adeno-associated virus and ensuring continued efficacy after multiple doses. These results reveal a shared lymphatic circuit able to mount a unified immune response between the posterior eye and the brain, highlighting an understudied immunological feature of the eye and opening up the potential for new therapeutic strategies in ocular and CNS diseases.

Nanoparticle-based drug delivery for the treatment of traumatic brain injury.

INTRODUCTION: Traumatic brain injuries (TBIs) impact the breadth of society and remain without any approved pharmacological treatments. Despite successful Phase II clinical trials, the failure of many Phase III clinical trials may be explained by insufficient drug targeting and retention, preventing the proper attainment of an observable dosage threshold. To address this challenge, nanoparticles can be functionalized to protect pharmacological payloads, improve targeted drug delivery to sites of injury, and can be combined with supportive scaffolding to improve secondary outcomes. AREAS COVERED: This review briefly covers the pathophysiology of TBIs and their subtypes, the current pre-clinical and clinical management strategies, explores the common models of focal, diffuse, and mixed traumatic brain injury employed in experimental animals, and surveys the existing literature on nanoparticles developed to treat TBIs. EXPERT OPINION: Nanoparticles are well suited to improve secondary outcomes as their multifunctionality and customizability enhance their potential for efficient targeted delivery, payload protection, increased brain penetration, low off-target toxicity, and biocompatibility in both acute and chronic timescales.

Brain Targeting, Antioxidant Polymeric Nanoparticles for Stroke Drug Delivery and Therapy.

Ischemic stroke is a leading cause of death and disability and remains without effective treatment options. Improved treatment of stroke requires efficient delivery of multimodal therapy to ischemic brain tissue with high specificity. Here, this article reports the development of multifunctional polymeric nanoparticles (NPs) for both stroke treatment and drug delivery. The NPs are synthesized using an reactive oxygen species (ROS)-reactive poly (2,2'-thiodiethylene 3,3'-thiodipropionate) (PTT) polymer and engineered for brain penetration through both thrombin-triggered shrinkability and AMD3100-mediated targeted delivery. It is found that the resulting AMD3100-conjugated, shrinkable PTT NPs, or ASPTT NPs, efficiently accumulate in the ischemic brain tissue after intravenous administration and function as antioxidant agents for effective stroke treatment. This work shows ASPTT NPs are capable of efficient encapsulation and delivery of glyburide to achieve anti-edema and antioxidant combination therapy, resulting in therapeutic benefits significantly greater than those by either the NPs or glyburide alone. Due to their high efficiency in brain penetration and excellent antioxidant bioactivity, ASPTT NPs have the potential to be utilized to deliver various therapeutic agents to the brain for effective stroke treatment.

Targeted disruption of tumor vasculature via polyphenol nanoparticles to improve brain cancer treatment.

Despite being effective for many other solid tumors, traditional anti-angiogenic therapy has been shown to be insufficient for the treatment of malignant glioma. Here, we report the development of polyphenol nanoparticles (NPs), which not only inhibit the formation of new vessels but also enable targeted disruption of the existing tumor vasculature. The NPs are synthesized through a combinatory iron-coordination and polymer-stabilization approach, which allows for high drug loading and intrinsic tumor vessel targeting. We study a lead NP consisting of quercetin and find that the NP after intravenous administration preferentially binds to VEGFR2, which is overexpressed in tumor vasculature. We demonstrate that the binding is mediated by quercetin, and the interaction of NPs with VEGFR2 leads to disruption of the existing tumor vasculature and inhibition of new vessel development. As a result, systemic treatment with the NPs effectively inhibits tumor growth and increases drug delivery to tumors.

Biocompatibility of nanomaterials and their immunological properties.

Nanomaterials (NMs) have revolutionized multiple aspects of medicine by enabling novel sensing, diagnostic, and therapeutic approaches. Advancements in processing and fabrication have also allowed significant expansion in the applications of the major classes of NMs based on polymer, metal/metal oxide, carbon, liposome, or multi-scale macro-nano bulk materials. Concomitantly, concerns regarding the nanotoxicity and overall biocompatibility of NMs have been raised. These involve putative negative effects on both patients and those subjected to occupational exposure during manufacturing. In this review, we describe the current state of testing of NMs including those that are in clinical use, in clinical trials, or under development. We also discuss the cellular and molecular interactions that dictate their toxicity and biocompatibility. Specifically, we focus on the reciprocal interactions between NMs and host proteins, lipids, and sugars and how these induce responses in immune and other cell types leading to topical and/or systemic effects.

Neuroinflammation, oxidative stress, and blood-brain barrier (BBB) disruption in acute Utah electrode array implants and the effect of deferoxamine as an iron chelator on acute foreign body response.

The use of intracortical microelectrode arrays has gained significant attention in being able to help restore function in paralysis patients and study the brain in various neurological disorders. Electrode implantation in the cortex causes vasculature or blood-brain barrier (BBB) disruption and thus elicits a foreign body response (FBR) that results in chronic inflammation and may lead to poor electrode performance. In this study, a comprehensive insight into the acute molecular mechanisms occurring at the Utah electrode array-tissue interface is provided to understand the oxidative stress, neuroinflammation, and neurovascular unit (astrocytes, pericytes, and endothelial cells) disruption that occurs following microelectrode implantation. Quantitative real time polymerase chain reaction (qRT-PCR) was used to quantify the gene expression at acute time-points of 48-hr, 72-hr, and 7-days for factors mediating oxidative stress, inflammation, and BBB disruption in rats implanted with a non-functional 4 × 4 Utah array in the somatosensory cortex. During vascular disruption, free iron released into the brain parenchyma can exacerbate the FBR, leading to oxidative stress and thus further contributing to BBB degradation. To reduce the free iron released into the brain tissue, the effects of an iron chelator, deferoxamine mesylate (DFX), was also evaluated.

Blood brain barrier (BBB)-disruption in intracortical silicon microelectrode implants.

Chronically implanted microelectrodes in the neural tissue elicit inflammatory responses that are time varying and have been shown to depend on multiple factors. Among these factors, blood brain barrier (BBB)-disruption has been hypothesized as one of the dominant factors resulting in electrode failure. A series of events that includes BBB and cell-membrane disruption occurs during electrode implantation that triggers multiple biochemical cascades responsible for microglial and astroglial activation, hemorrhage, edema, and release of pro-inflammatory neurotoxic cytokines that causes neuronal degeneration and dysfunction. Typically, microwire arrays and silicon probes are inserted slowly into the neural tissue whereas the silicon Utah MEAs (UMEA) are inserted at a high speed using a pneumatic inserter. In this work, we report the sequelae of electrode-implant induced cortical injury at various acute time points in UMEAs implanted in the brain tissue by quantifying the expression profile for key genes mediating the inflammatory response and tight junction (TJ) and adherens junction (AJ) proteins that form the BBB and are critical to the functioning of the BBB. Our results indicated upregulation of most pro-inflammatory genes relative to naïve controls for all time points. Expression levels for the genes that form the TJ and AJ were downregulated suggestive of BBB-dysfunction. Moreover, there was no significant difference between stab and implant groups suggesting the effects of UMEA insertion-related trauma in the brain tissue. Our results provide an insight into the physiological events related to neuroinflammation and BBB-disruption occurring at acute time-points following insertion of UMEAs.