Micro/nanosystems for controllable drug delivery to the brain

Abstract

Drug delivery to the brain is crucial in the treatment for central nervous system disorders. While significant progress has been made in recent years, there are still major challenges in achieving controllable drug delivery to the brain. Unmet clinical needs arise from various factors, including controlled drug transport, handling large drug doses, methods for crossing biological barriers, the use of imaging guidance, and effective models for analyzing drug delivery. Recent advances in micro/nanosystems have shown promise in addressing some of these challenges. These include the utilization of microfluidic platforms to test and validate the drug delivery process in a controlled and biomimetic setting, the development of novel micro/nanocarriers for large drug loads across the blood-brain barrier, and the implementation of micro-intervention systems for delivering drugs through intraparenchymal or peripheral routes. In this article, we present a review of the latest developments in micro/nanosystems for controllable drug delivery to the brain. We also delve into the relevant diseases, biological barriers, and conventional methods. In addition, we discuss future prospects and the development of emerging robotic micro/nanosystems equipped with directed transportation, real-time image guidance, and closed-loop control.

Graphical abstract

Figure 1

Biological barrier in the brain Biological barriers in the brain include the arachnoid barrier, the blood-cerebrospinal fluid barrier, and the blood-brain barrier. The blood-brain barrier consists of endothelial cells, pericytes, astrocyte endfeet, and basement membranes, distinguished by tight junctions between endothelial cells.

Figure 2

Microfluidic systems for in vitro models Microfluidic systems offer the capability to create both artificial and self-forming in vitro models. Artificial scaffold designs primarily encompass porous membranes, microchannels, micropillars, and tubular configurations. Meanwhile, self-forming in vitro models predominantly include vasculogenesis designs, organoids, and organoids-on-chip. Microscopic images were reproduced from Campisi and co-workers.^,,,,,, Copyright 2020, Springer Nature; 2019, Wiley Periodicals; 2021, Springer Nature; 2018, Wiley-VCH; 2018, Elsevier; 2013, Springer Nature; 2017, The Royal Society of Chemistry.

Figure 3

Artificial structures and self-forming structures of μBBBs (A) Schematic of a vertically designed μBBBs containing three types of cells. Reproduced from Ahn et al. Copyright 2020, Springer Nature. (B) Schematic diagram (left) and bright-field images (right) of a microchannel-profiled μBBB model. Scale bars, 100 μm. Reproduced from Fan et al. Copyright 2023, The Royal Society of Chemistry. (C) A micropillars-designed μBBB to mimic damage to nerve cells by thrombin influx through a damaged BBB. Dead cells are shown in red. Scale bars, 200 μm. Reproduced from Shin et al. Copyright 2019, Wiley-VCH. (D) Fabrication schematic (left) and SEM image (right) of a TPP printed tubular μBBB design. Reproduced from Marino et al. Copyright 2018, Wiley-VCH. (E) Schematic of a tubular design μBBB + GBM (left). Fluorescent images showing the uptake of DOX by GBM spheres (right). Reproduced from Seo et al. Copyright 2022, Wiley-VCH. (F) Schematic representation of a vasculogenesis BBB microvascular network model that mimics the microvascular structure in the brain environment. Reproduced from Campisi et al. Copyright 2018, Elsevier. (G) Schematic diagram of the angiogenesis microfluidic chip. Reproduced from Kim et al. Copyright 2021, Elsevier. (H) Representative confocal images showing the organization of human astrocytes (white), HBVP (blue), and (left) primary HBMEC (red) or (right) immortalized human cerebral microvascular ECs (hCMEC/D3; green) when co-cultured to form a spheroid. Reproduced from Cho et al. Copyright 2017, Springer Nature. (I) A cutaway rendering of the microfluidic spheroid array (top). Overview of the established 3D BBB model system (bottom). The arrows indicate the transport of the drug. Reproduced from Eilenberger et al. Copyright 2021, Wiley-VCH.

Figure 4

Micro/nanomatters for vasculature-brain drug delivery Both biological carriers and artificial micro/nanomatters can cross the BBB through intercellular and intracellular routes. The BBB, along with micro/nano materials, can be controlled using external stimuli, such as magnetic fields, electroporation, focused ultrasound, and photothermal.

Figure 5

Artificial micro/nanomatters (A) Schematic that shows how engineered neutrophil target glioma after intravenous injection into mice. Reproduced from Xue et al. Copyright 2017, Springer Nature. (B) AAV9 capsid model showing the insertion site for CPPs (top). Representative images of mouse brain regions showing successfully transfected cells by AAV.CPP.21 (white dots) (bottom). Reproduced from Yao et al. Copyright 2022, Springer Nature. (C) Schematic of the microrobots (top). Ex vivo model of a brain blood vessel and the magnetic field control system (bottom). Reproduced from Jeon et al. Copyright 2019, American Association for the Advancement of Science. (D) After CpG-EXO/TGM enters the blood circulation, the TfR on its surface can combine with free Tf in the blood, so that CpG-EXO/TGM is endowed with the ability to target BBB and GBM cells. Reproduced from Cui et al. Copyright 2023, American Chemical Society. (E) Schematic illustration of formulating NT-lipidoid-doped LNPs for cargo delivery into the brain. Reproduced from Ma et al. Copyright 2020, American Association for the Advancement of Science. (F) Schematic of active therapeutics of dual-responsive neutrobots in vivo. Reproduced from Zhang et al. Copyright 2021, American Association for the Advancement of Science. (G) Schematic representation of small-molecule-loaded liposomes tethered to microbubbles. Reproduced from Ozdas et al. Copyright 2020, Springer Nature.

Figure 6

Manipulation of the micro/nanomatters and the BBB (A) Schematic representation of the non-invasive optoacoustic tomography of magnetic microrobots inside the murine brain vasculature. Reproduced from Wrede et al. Copyright 2022, American Association for the Advancement of Science. (B) Schematic representation of reversible modulation of the BBB by laser stimulation of molecularly targeted nanoparticles (left). Electron microscopy imaging of lanthanum diffusion into the basement membrane (∗) and interstitial space (empty arrowheads) (bottom). Reproduced from Li et al Copyright 2021, American Chemical Society. (C) Experimental schemes for nanoparticle administration and HIFU irradiation (top). Representative immunofluorescence images of midbrain sections co-stained for ZO-1 (red), CD31 (green), and nuclei (blue) (bottom). Scale bars, 30 μm. Reproduced from Kim et al. Copyright 2023, Springer Nature. (D) MRI demonstration of BBB opening and closure. Axial T1-weighted gadolinium MRIs of patient 5 at (1) baseline, (2) immediately after stage 2 sonication and BBB opening, and (3) at 24 h after the procedure. Reproduced from Lipsman et al. Copyright 2018, Springer Nature. (E) The electric field overlay (200 V) on the coronal plane corresponds to the center of the electrode device. (F) Rat brain histology after different voltage treatments. Reproduced from Mahmood et al. Copyright 2015, Informa UK Limited.

Figure 7

Scheme of microsystems for invasive drug delivery Microsystems can facilitate the invasive delivery of drugs to the brain, including intracerebral administration, intranasal delivery, intrathecal injection, and transvascular intervention. Note: this figure is modified from Furtado et al.

Figure 8

Microsystems for invasive drug delivery (A) Schematic illustration of stereotaxic surgery for intracerebroventricular (i.c.v.) injection, CSF-brain barrier, and CSF-blood barrier. Reproduced from Kim et al. Copyright 2020, Elsevier. (B) Schematic illustration of penetrative and sustained drug delivery to deep brain tumors from the intracortical hydrogel nanocomposite by the magnetic activation for mild hyperthermia. Reproduced from Kang et al. Copyright 2023, American Chemical Society. (C) Distribution of nanoparticles in the brain after CED (left). Bioluminescent IVIS images of representative mice (right). Reproduced from Wang et al. Copyright 2021, Springer Nature. (D) Schematic and confocal image of the structure of a micromesh, PLGA strands (green), and the PVA layer carrying RhB nanoparticles (red). Reproduced from Di Mascolo et al. Copyright 2021, Springer Nature. (E) Multimodality fiber probe fabrication and characterization. Reproduced from Canales et al. Copyright 2015, Springer Nature. (F) Schematic of the intranasal administration and magnetic actuation of cellbots (top). Sequential migration and engraftment of the cellbots from the injection site (olfactory bulb) to the cerebral cortex (bottom). Reproduced from Jeon et al. Copyright 2021, Wiley-VCH. (G) Representative PET images of agrin in mice at 30 min after intrathecal injection. Reproduced from Li et al. Copyright 2020, Wiley-VCH. (H) Reverse transport process of rAAV2-Retro to the CNS after intramuscular injection. Reproduced from Chen et al. Copyright 2020, Elsevier.