The blood-brain barrier (BBB) is a highly selective membrane that protects the central nervous system from harmful substances while allowing essential nutrients to pass through. Its tight junctions and efflux transporters pose a significant challenge for delivering therapeutic agents to the brain. Nanoparticles (NPs) have emerged as promising tools to overcome this barrier through various strategies, including receptor-mediated transcytosis, adsorptive-mediated transport, and temporary BBB disruption. These approaches enable targeted drug delivery for treating glioblastoma, neurodegenerative diseases, and other neurological disorders while minimizing systemic side effects.

Receptor-mediated transcytosis exploits endogenous transport pathways by functionalizing NPs with ligands that bind to receptors expressed on BBB endothelial cells. Transferrin receptors (TfR) are widely targeted due to their overexpression in brain endothelial cells and certain cancers. Transferrin-coated NPs or anti-TfR antibody-conjugated NPs bind to TfR, triggering internalization and transport across the BBB. Studies show that TfR-targeted NPs can enhance brain uptake of drugs by up to 10-fold compared to non-targeted NPs. Similarly, low-density lipoprotein (LDL) receptors are targeted using angiopep-2, a peptide ligand that binds to LDL receptor-related protein 1 (LRP1). Angiopep-2-conjugated NPs have demonstrated improved brain delivery of chemotherapeutics like paclitaxel in glioblastoma models, with a 2- to 3-fold increase in accumulation compared to free drug.

Adsorptive-mediated transcytosis relies on electrostatic interactions between positively charged NPs and the negatively charged BBB surface. Cationic polymers like chitosan or cell-penetrating peptides (e.g., TAT) facilitate this process. For example, polysorbate 80-coated NPs adsorb apolipoproteins from the bloodstream, mimicking LDL particles and promoting uptake via LDL receptors. This strategy has been used to deliver drugs like doxorubicin across the BBB, achieving therapeutic concentrations in brain tumors. However, excessive positive charge can lead to nonspecific binding and toxicity, necessitating careful optimization of surface properties.

Temporary BBB disruption is another approach, often employed for large-molecule delivery. Focused ultrasound (FUS) combined with microbubbles can transiently open the BBB by inducing mechanical stress on endothelial tight junctions. Preclinical studies report a 4- to 5-fold increase in NP accumulation in the brain following FUS treatment. Alternatively, hyperosmotic solutions like mannitol cause endothelial cell shrinkage, creating temporary gaps for NP passage. While effective, these methods require precise control to avoid neuroinflammation or neuronal damage.

Material selection plays a critical role in NP design. Polymeric NPs, such as poly(lactic-co-glycolic acid) (PLGA), are commonly used due to their biodegradability and tunable release kinetics. Liposomes, especially those coated with polysorbate 80, show high BBB penetration and are FDA-approved for certain applications. Gold NPs and silica NPs are explored for their imaging capabilities, enabling real-time tracking of delivery efficiency. For example, gold NPs conjugated with angiopep-2 have been used for both drug delivery and computed tomography (CT) imaging in glioblastoma.

Applications in glioblastoma highlight the potential of NP-based delivery. Temozolomide-loaded NPs targeting TfR or LRP1 have shown enhanced tumor penetration and reduced off-target effects in preclinical models. Similarly, siRNA-loaded NPs silencing oncogenic pathways like EGFRvIII demonstrate promise in overcoming chemoresistance. In neurodegenerative diseases, NPs delivering antioxidants (e.g., curcumin) or gene-editing tools (e.g., CRISPR-Cas9) are being investigated for Alzheimer’s and Parkinson’s. For instance, NPs encapsulating dopamine precursors improve motor function in Parkinson’s models by achieving sustained release in the striatum.

Neurotoxicity remains a concern, particularly with metallic NPs like silver or iron oxide, which may induce oxidative stress or inflammation. Surface coatings (e.g., polyethylene glycol, PEG) mitigate toxicity by reducing immune recognition. Rigorous biodistribution studies are essential to assess long-term safety, as even biodegradable materials may accumulate in peripheral organs.

Imaging-guided delivery integrates diagnostics and therapy (theranostics). Magnetic resonance imaging (MRI)-visible NPs, such as iron oxide NPs coated with targeting ligands, enable real-time monitoring of BBB crossing and tumor targeting. Fluorescent quantum dots are used in two-photon microscopy to track NP distribution in brain tissue. These tools optimize dosing regimens and minimize invasive procedures.

In summary, NP strategies for BBB penetration leverage biological pathways, material engineering, and imaging technologies to address unmet needs in neurology. Receptor-mediated and adsorptive transcytosis offer targeted delivery, while temporary disruption methods enable large payload transport. Glioblastoma and neurodegenerative diseases stand to benefit significantly, though neurotoxicity risks must be carefully managed. Future advancements will likely focus on multifunctional NPs combining targeting, therapy, and imaging in a single platform.