Recent progress on nanotechnologies for enhancing blood-brain barrier permeability

Abstract

The blood-brain barrier (BBB) is a substantial impediment to effectively delivering central nervous system (CNS) therapies. In this review, we provide a comprehensive dissection of the BBB's elaborate structure and function and discuss the inherent limitations of conventional drug delivery mechanisms due to its impermeability. We summarized the creative deployment of nanocarriers, the astute modification of small molecules to bolster their CNS penetration capabilities as well as the burgeoning potential of magnetic nanoparticles and optical techniques that are positioned to enable more precise and targeted drug delivery across the BBB and we discuss the current clinical application of some nanomedicines. In addition, we emphasize the indispensable role of artificial intelligence in designing novel materials and the paramount significance of interdisciplinary research in surmounting clinical challenges associated with BBB penetration. Our review meticulously integrates these insights to accentuate the impact of nanotechnological innovations in BBB research and CNS disease management. It presents a promising trajectory for the evolution of patient care in neurological disorders and suggests that these scientific strides could lead to more efficacious treatments and improved outcomes for those afflicted with such conditions.

Keywords: biological activity; imaging agents; nanoparticles; nanotechnology; polymers.

FIGURE 1

A timeline of significant milestones in BBB‐related nanotechnology research. BBB, blood‐brain barrier.

FIGURE 2

Barriers of the CNS. The three main barriers of the CNS include (a) the arachnoid barrier, (b) the blood–brain barrier, and (c) the blood–cerebro‐spinal‐fluid barrier, all of which are identifiable in (d) a schematic coronal brain section. Of the three barriers, the BBB maintains the closest proximity to the brain parenchyma, and therefore offers the most viable opportunity for CNS drug delivery. BBB, blood‐brain barrier; CNS, central nervous system. Reproduced with permission. Copyright 2018, Wiley‐Blackwell.

FIGURE 3

Transport processes at the capillary endothelium of BBB. (a) Receptor‐mediated transcytosis; (b) paracellular diffusion; (c) transcellular diffusion; (d) efflux pumps; (e) adsorptive trans‐ cytosis; (f) transporter‐mediated transcytosis. BBB, blood‐brain barrier; LDL, low‐density lipoproteins. Reproduced with permission. Copyright 2021, Science Press.

FIGURE 4

Schematic illustration of recent advancements in nanotechnology for enhancing BBB permeability that will be discussed covering innovations in nano‐carrier structures, targeting strategies, imaging‐guided BBB opening techniques, and clinical complexities. It also explores future research directions, including the role of AI in material design and interdisciplinary collaboration, concluding with the impact of these developments on BBB research and CNS disease treatment. BBB, blood‐brain barrier; CNS, central nervous system.

FIGURE 5

Schematic illustration of magnetic iron oxide nanoparticles (MIONPs) for brain disease imaging and drug delivery. Reproduced with permission. Copyright 2023, Elsevier.

FIGURE 6

Mechanisms of exchange of small molecules across the BBB. BBB, blood‐brain barrier. Reproduced with permission. Copyright 2021, American Chemical Society.

FIGURE 7

By covalently linking Ce6 with luminol, the Ce6‐luminol (CL) molecule with self‐illuminating potential was synthesized and encapsulated into c(RGDyK) peptide‐modified paclitaxel prodrug nano‐ particles to form a nano system (CL@RNP_PTX). CP nanodots with pH‐dependent hydroxyl radical (·OH) generation properties were synthesized and embedded into the hydroxypropyl chitin hydrogel 3D framework with CL@RNP_PTX to construct a multifunctional nanoparticle‐hydrogel hybrid drug carrier for the treatment of postoperative glioma. Reproduced with permission. Copyright 2022, American Chemical Society.

FIGURE 8

Picosecond stimulation of Tight junction‐targeted nanoparticles reversibly modulate BBB permeability. BBB, blood‐brain barrier. Reproduced with permission. Copyright 2021, American Chemical Society.

FIGURE 9

Schematic illustration of ultrasound‐mediated opening of tight junctions. Reproduced with permission. Copyright 2018, Wiley–Blackwell.