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Artificial intelligence and machine learning driven nanorobotics for targeted brain delivery: Redefining blood-brain barrier navigation.
The blood-brain barrier (BBB) plays a central role in preserving central nervous system (CNS) homeostasis, and its dysfunction is implicated in various neurological disorders and brain malignancies. To emulate the complex architecture and signaling environment of the BBB, researchers have developed advanced in vitro models incorporating three-dimensional (3D) cell cultures, organoid technologies, and microfluidic platforms. These innovations have significantly expanded the scope of neuropharmacological research, particularly in understanding BBB transport mechanisms and enhancing drug delivery strategies. The following review highlights the integration of biomolecular tools and nanomaterial-based engineering approaches to facilitate the targeted delivery of theranostic agents across the BBB. Specifically, it discusses the emerging role of nanorobots and nanosystems in mediating cellular interactions that enable precise modulation and penetration of the barrier. Case studies addressing therapeutic applications in brain tumors and cognitive dysfunctions are also evaluated. Moreover, the review explores the intersection of artificial intelligence (AI), machine learning (ML), and robotics, which together offer transformative potential in designing intelligent nanorobots capable of efficient and safe BBB traversal. Collectively, this work serves as a consolidated resource for clinicians, biomedical scientists, and technologists aiming to develop innovative strategies for BBB-targeted therapies and biopharmaceutical applications.
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Neurological Manifestations of SARS-CoV-2.
Neurocognitive symptoms have emerged as notable sequelae of SARS-CoV-2 infection (COVID-19). Although primarily a respiratory virus, SARS-CoV-2 has been associated with central nervous system (CNS) changes observed in both clinical and experimental settings. To better understand these effects and their pathological mechanisms, we conducted a systematic literature search of published studies and employed a qualitative, analytical approach to identify and synthesize key findings from peer-reviewed studies, including large-scale retrospective clinical cohorts, human autopsy reports, animal models (murine, non-human primate), and in vitro brain organoid systems. While viral components were detected in post mortem central nervous system tissues, COVID-19 neuropathology appears to stem primarily from immune-mediated inflammation and vascular injury rather than direct CNS infection. Persistent glial activation and BBB disruption may underlie the long-term neurological symptoms reported in long COVID-19. Although animal models offer mechanistic insight, species-specific differences necessitate cautious extrapolation to human pathology. Further investigation into the chronic effects of SARS-CoV-2 on the brain is essential to guide long-term clinical management and therapeutic development.
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[The reaction of the neocortical structures in the seal Pusa sibirica to a prolonged stay under water].
Using light and electron microscopic techniques, structural and functional changes in the neurones and glia of the Baikal seal neocortex were revealed during diving. These changes include shifts in tinctorial properties of cells, in the number of dendritic spines, cell ultrastructure (condensation and redistribution of nuclear chromatin, swelling of organoids, etc.). These changes are both non-specific and reversible, indicating high reserve capacities of the brain in this species.
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Complete inhibition of ABCB1 and ABCG2 at the blood-brain barrier by co-infusion of erlotinib and tariquidar to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib.
P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) restrict at the blood-brain barrier (BBB) the brain distribution of the majority of currently known molecularly targeted anticancer drugs. To improve brain delivery of dual ABCB1/ABCG2 substrates, both ABCB1 and ABCG2 need to be inhibited simultaneously at the BBB. We examined the feasibility of simultaneous ABCB1/ABCG2 inhibition with i.v. co-infusion of erlotinib and tariquidar by studying brain distribution of the model ABCB1/ABCG2 substrate [11C]erlotinib in mice and rhesus macaques with PET. Tolerability of the erlotinib/tariquidar combination was assessed in human embryonic stem cell-derived cerebral organoids. In mice and macaques, baseline brain distribution of [11C]erlotinib was low (brain distribution volume, VT,brain < 0.3 mL/cm3). Co-infusion of erlotinib and tariquidar increased VT,brain in mice by 3.0-fold and in macaques by 3.4- to 5.0-fold, while infusion of erlotinib alone or tariquidar alone led to less pronounced VT,brain increases in both species. Treatment of cerebral organoids with erlotinib/tariquidar led to an induction of Caspase-3-dependent apoptosis. Co-infusion of erlotinib/tariquidar may potentially allow for complete ABCB1/ABCG2 inhibition at the BBB, while simultaneously achieving brain-targeted EGFR inhibition. Our protocol may be applicable to enhance brain delivery of molecularly targeted anticancer drugs for a more effective treatment of brain tumors.
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Moral considerability of brain organoids from the perspective of computational architecture.
Human brain organoids equipped with complex cytoarchitecture and closed-loop feedback from virtual environments could provide insights into neural mechanisms underlying cognition. Yet organoids with certain cognitive capacities might also merit moral consideration. A precautionary approach has been proposed to address these ethical concerns by focusing on the epistemological question of whether organoids possess neural structures for morally-relevant capacities that bear resemblance to those found in human brains. Critics challenge this similarity approach on philosophical, scientific, and practical grounds but do so without a suitable alternative. Here, I introduce an architectural approach that infers the potential for cognitive-like processing in brain organoids based on the pattern of information flow through the system. The kind of computational architecture acquired by an organoid then informs the kind of cognitive capacities that could, theoretically, be supported and empirically investigated. The implications of this approach for the moral considerability of brain organoids are discussed.
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Microfluidics for Neuronal Cell and Circuit Engineering.
The widespread adoption of microfluidic devices among the neuroscience and neurobiology communities has enabled addressing a broad range of questions at the molecular, cellular, circuit, and system levels. Here, we review biomedical engineering approaches that harness the power of microfluidics for bottom-up generation of neuronal cell types and for the assembly and analysis of neural circuits. Microfluidics-based approaches are instrumental to generate the knowledge necessary for the derivation of diverse neuronal cell types from human pluripotent stem cells, as they enable the isolation and subsequent examination of individual neurons of interest. Moreover, microfluidic devices allow to engineer neural circuits with specific orientations and directionality by providing control over neuronal cell polarity and permitting the isolation of axons in individual microchannels. Similarly, the use of microfluidic chips enables the construction not only of 2D but also of 3D brain, retinal, and peripheral nervous system model circuits. Such brain-on-a-chip and organoid-on-a-chip technologies are promising platforms for studying these organs as they closely recapitulate some aspects of in vivo biological processes. Microfluidic 3D neuronal models, together with 2D in vitro systems, are widely used in many applications ranging from drug development and toxicology studies to neurological disease modeling and personalized medicine. Altogether, microfluidics provide researchers with powerful systems that complement and partially replace animal models.
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Modeling hypothalamic pathophysiology in vitro for metabolic, circadian, and sleep disorders.
The hypothalamus, a small and intricate brain structure, orchestrates numerous neuroendocrine functions through specialized neurons and nuclei. Disruption of this complex circuitry can result in various diseases, including metabolic, circadian, and sleep disorders. Advances in in vitro models and their integration with new technologies have significantly benefited research on hypothalamic function and pathophysiology. We explore existing in vitro hypothalamic models and address their challenges and limitations as well as translational findings. We also highlight how collaborative efforts among multidisciplinary teams are essential to develop relevant and translational experimental models capable of replicating intricate neural circuits and neuroendocrine pathways, thereby advancing our understanding of therapeutic targets and drug discovery in hypothalamus-related disorders.
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Choroid plexus mast cells drive tumor-associated hydrocephalus.
Tumor-associated hydrocephalus (TAH) is a common and lethal complication of brain metastases. Although other factors beyond mechanical obstructions have been suggested, the exact mechanisms are unknown. Using single-nucleus RNA sequencing and spatial transcriptomics, we find that a distinct population of mast cells locate in the choroid plexus and dramatically increase during TAH. Genetic fate tracing and intracranial mast-cell-specific tryptase knockout showed that choroid plexus mast cells (CPMCs) disrupt cilia of choroid plexus epithelia via the tryptase-PAR2-FoxJ1 pathway and consequently increase cerebrospinal fluid production. Mast cells are also found in the human choroid plexus. Levels of tryptase in cerebrospinal fluid are closely associated with clinical severity of TAH. BMS-262084, an inhibitor of tryptase, can cross the blood-brain barrier, inhibit TAH in vivo, and alleviate mast-cell-induced damage of epithelial cilia in a human pluripotent stem-cell-derived choroid plexus organoid model. Collectively, we uncover the function of CPMCs and provide an attractive therapy for TAH.
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A comparative view of human and mouse telencephalon inhibitory neuron development.
Human GABAergic inhibitory neurons (INs) in the telencephalon play crucial roles in modulating neural circuits, generating cortical oscillations, and maintaining the balance between excitation and inhibition. The major IN subtypes are based on their gene expression profiles, morphological diversity and circuit-specific functions. Although previous foundational work has established that INs originate in the ganglionic eminence regions in mice, recent studies have questioned origins in humans and non-human primates. We review the origins of INs in mice and compare with recent findings from primary human prenatal brain tissue culture experiments and lineage analysis from somatic variants in neurotypical human cadavers and human brain organoids. Together, these studies suggest potential primate- or human-specific processes that may have been overlooked in mouse models and could have implications for brain disorders.
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Brain Extracellular Matrix-Based Electronic Brain Biochip.
To monitor neuronal activity with high fidelity, in vitro models must recapitulate not only the cellular composition but also the three-dimensional (3D) microenvironment of the brain. Here, we present an electronic brain biochip that integrates animal-derived decellularized extracellular matrix (dECM) hydrogels with flexible, multichannel electrodes to build a multilayer 3D neural network in which each layer can be independently monitored. Brain dECM hydrogels provide tissue-like biochemical and structural cues that accelerate neurite outgrowth and neural connectivity between layers, enabling the formation of functionally active 3D networks within 3 weeks. We use a low-cost, readily available dECM source from porcine brain tissue, upcycling biological waste into high-value neural scaffolds without compromising biocompatibility. The dECM hydrogels are compatible with both rat primary neurons and hiPSC-derived neurons. Flexible electrode interfaces support real-time, multichannel electrophysiological recording and controlled chemical stimulation. The combination of dECM scaffolding and flexible electrode interfaces supports signal capture throughout the 3D network volume. Functional assays under chemical stimulation reveal bursting and synchronized activity in which all layers participate. By coupling a dECM-based, 3D neural architecture to flexible, multichannel electronics, this work establishes a scalable "electronic organoid" platform for the study of neuronal dynamics and neuropharmacology. Collectively, these advances represent an important step toward artificial brain models that bridge the gap between engineered neural tissues and functional neurobiology.