K16ApoE-mediated delivery across the blood-brain barrier: mechanisms, applications, and translational challenges.

CA-IV-directed small-molecule shuttle enables targeted brain delivery of biologics.

The blood-brain barrier (BBB) presents a challenge for central nervous system (CNS) therapies. Receptor-mediated transcytosis offers a solution, but existing receptor targets are ubiquitous across CNS and peripheral tissues, causing unintended exposure. We identified carbonic anhydrase IV (CA-IV) as a brain-enriched receptor enabling engineered viral capsids to cross the BBB. However, it is unclear whether CA-IV can also mediate non-viral delivery. We thus designed a reactive small-molecule shuttle, derived from an FDA-approved binder, that couples to proteins and oligonucleotides in a single step. We validated the binding of conjugated molecules to multiple mammalian CA-IV orthologs and subsequent internalization in cell-based assays. After systemic dosing, CA-IV-targeted antibody conjugates crossed the BBB in mice and neonatal macaques, preferentially accumulating in the brain and sustaining parenchymal levels for at least 7 days. This BrainCAB (Brain access through Carbonic Anhydrase-binder Bioconjugation) technology offers a compact, modular shuttle for selective and prolonged CNS delivery of large molecules.

Breaking the Blood-Brain Barrier: Nanoparticle Innovations in Brain Drug Delivery

The blood–brain barrier (BBB), a highly specialized and selective interface, is essential for preserving the homeostasis of the central nervous system (CNS) but also presents a significant barrier to the efficient administration of medications for neurological conditions. The BBB limits the passage of most therapeutic drugs due to its tight junctions, efflux transporters, and regulated permeability. As a result, there are few therapy choices for ailments including brain tumors, Parkinson's disease, Alzheimer's disease, stroke, and other CNS-related disorders. Conventional drug delivery methods, such as altering pharmaceuticals chemically and using intrusive administration. Drug delivery technologies based on nanotechnology have been a viable way to get over BBB-related restrictions in recent years. This paper offers a thorough summary of methods for improving drug transport across the blood-brain barrier that are mediated by nanoparticles. The structural features, BBB penetration mechanisms, and therapeutic applications of a variety of nanocarrier systems—including liposomes, polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, polymeric micelles, dendrimers, inorganic nanoparticles, and biomimetic carriers like exosomes—are examined. Receptor-mediated transcytosis, surface modification techniques, and biomimetic designs that enhance targeting effectiveness and biocompatibility are given particular attention. Furthermore, the review highlights key applications of nanoparticle-based systems in the management of major neurological disorders while critically addressing existing safety concerns, translational challenges, and regulatory limitations. Overall, this article underscores the potential of nanocarrier-based platforms to revolutionize CNS drug delivery and emphasizes future perspectives aimed at improving clinical translation and therapeutic outcome.

Exosomes in brain diseases: Mechanisms, advances, and perspectives

The blood–brain barrier (BBB) remains a major biological obstacle limiting the effective delivery of therapeutics for central nervous system (CNS) disorders. Although conventional drug delivery approaches have achieved continuous advances, their clinical translation is frequently restricted by limited brain penetration, insufficient target specificity, and systemic adverse effects. Exosomes, endogenous extracellular vesicles (EVs) involved in intercellular communication, have emerged as promising candidates for CNS therapeutic delivery owing to their favorable biocompatibility, relatively low immunogenicity, and potential ability to interact with biological barriers. In this review, we first summarize the structural characteristics of the BBB and the mechanisms underlying exosome–BBB interactions and transport. We then discuss current strategies for exosome isolation, characterization, and engineering, highlighting how these approaches influence therapeutic performance and translational feasibility. Subsequently, we analyze recent advances in exosome-based therapies for major CNS disorders, including neurodegenerative diseases, brain tumors, and ischemic stroke, with emphasis on how distinct pathological environments guide the design of exosome cargos, targeting strategies, and functional modifications. Finally, we discuss key challenges associated with clinical translation, including manufacturing standardization, pharmacokinetic evaluation, safety assessment, and regulatory considerations. This review provides a pathology-driven and engineering-guided perspective for understanding the rational design and future development of exosome-based therapeutics for CNS disorders.

Efficient brain delivery and sustained retention of antibodies via dual targeting of blood–brain barrier and intra-brain proteins

ABSTRACT Efficient delivery of therapeutic antibodies to the brain has been increasingly achieved using receptor-mediated transcytosis (RMT) approaches such as transferrin receptor (TfR)-mediated shuttle systems. Moreover, a strategy for enhancing brain retention has recently emerged as a focus of attention to overcome the rapid clearance of TfR shuttles from the brain. Here, we propose a novel approach that combines binding to intra-brain proteins, such as myelin oligodendrocyte glycoprotein (MOG), cell adhesion molecule 3, and chondroitin sulfate proteoglycan 5, for sustained retention in the brain with binding to blood–brain barrier (BBB) proteins, such as TfR and insulin-like growth factor 1 receptor, for enhanced BBB permeability. A mouse pharmacokinetic study demonstrated that the anti-MOG/TfR antibody reached a higher maximum concentration and maintained higher concentrations in the brain for 4 months than anti-MOG and anti-TfR antibodies. In immunohistochemistry and brain 3D-imaging study, the anti-MOG/TfR antibody distributed throughout the whole brain, suggesting it penetrates the BBB across the whole brain parenchyma and is retained there. Finally, this antibody technology was applied to brain delivery of neprilysin, an enzyme that degrades amyloid beta, demonstrating that it can enhance both the brain exposure and the pharmacodynamic effect of the potential therapeutic molecule. In conclusion, the concept of achieving sustained high brain exposure by combining BBB transport with enhanced brain retention was shown to be broadly applicable. This novel antibody technology platform is expected to deliver and retain various therapeutic molecules efficiently within the brain, addressing critical challenges in drug development for the central nervous system.

Esterified Cholesterol Conjugates Enable LNP-Mediated mRNA Delivery to the Blood-Brain Barrier Following Intravenous Administration.

The blood-brain barrier (BBB) plays a critical role in maintaining central nervous system homeostasis by regulating molecular and cellular exchange between the brain and peripheral circulation. While most delivery strategies focus on crossing the BBB, targeting brain endothelial cells directly may offer a complementary and more controlled alternative for therapeutic intervention. This study presents a ligand-free lipid nanoparticle (LNP) platform that enables efficient mRNA delivery to the brain endothelium via systemic administration. A modular synthesis strategy was used to generate a chemically diverse library of cholesterol-based lipids. Screening of 486 LNPs identified an optimized four-component formulation consisting of C6O2B2 (novel cholesterol-based lipid), DODAP, DSPC, and DMG-PEG, which achieves high transfection efficiency in brain endothelial cells without the incorporation of free cholesterol or disruption of BBB integrity and function, such as those utilized in focused ultrasound (FUS) techniques. This BBB-targeting LNP platform avoids neuronal and glial transfection, thereby offering a noninvasive, and scalable approach for cerebrovascular gene delivery. The work establishes a new class of cholesterol-based lipids and provides a foundation for next-generation RNA therapeutics targeting BBB-associated diseases.

pH-dependent anti-TfR1 NANOBODY® molecules deliver efficacious oligonucleotide payloads to muscle and CNS tissues