Self-Assembled Nanoscale Materials for Neuronal Regeneration: A Focus on BDNF Protein and Nucleic Acid Biotherapeutic Delivery

Abstract

Enabling challenging applications of nanomedicine and precision medicine in the treatment of neurodegenerative disorders requires deeper investigations of nanocarrier-mediated biomolecular delivery for neuronal targeting and recovery. The successful use of macromolecular biotherapeutics (recombinant growth factors, antibodies, enzymes, synthetic peptides, cell-penetrating peptide-drug conjugates, and RNAi sequences) in clinical developments for neuronal regeneration should benefit from the recent strategies for enhancement of their bioavailability. We highlight the advances in the development of nanoscale materials for drug delivery in neurodegenerative disorders. The emphasis is placed on nanoformulations for the delivery of brain-derived neurotrophic factor (BDNF) using different types of lipidic nanocarriers (liposomes, liquid crystalline or solid lipid nanoparticles) and polymer-based scaffolds, nanofibers and hydrogels. Self-assembled soft-matter nanoscale materials show favorable neuroprotective characteristics, safety, and efficacy profiles in drug delivery to the central and peripheral nervous systems. The advances summarized here indicate that neuroprotective biomolecule-loaded nanoparticles and injectable hydrogels can improve neuronal survival and reduce tissue injury. Certain recently reported neuronal dysfunctions in long-COVID-19 survivors represent early manifestations of neurodegenerative pathologies. Therefore, BDNF delivery systems may also help in prospective studies on recovery from long-term COVID-19 neurological complications and be considered as promising systems for personalized treatment of neuronal dysfunctions and prevention or retarding of neurodegenerative disorders.

Keywords: biotherapeutics; brain-derived neurotrophic factor (BDNF); lipid nanoparticles; nanocarriers; nanofibers; nanomedicine for growth factor delivery; neuroprotective assemblies.

Figure 1

Uptake mechanisms involved in the transport of therapeutic proteins from the nasal cavity directly to the brain via the olfactory nerve pathway (Reprinted with permission from Ref [70]. Copyright 2018 Elsevier).

Figure 2

Schematic presentation of functionalized nanoparticles (NPs) and nanoscale materials for targeted drug delivery: polymeric nanoparticles of biodegradable nature (PLGA or PLGA-PEG-PLGA), inorganic silica and gold nanoparticles functionalized with surface-anchored ligands, nanofibers for sustained release of neurotrophic compounds, and lipid-based self-assembled liquid crystalline nanocarriers (liposomes and cubosomes) for protein and gene delivery.

Figure 3

Schematic presentation of the microstructure of the blood–brain barrier (BBB) and possible mechanisms of biomolecule passage to the central nervous system (Reprinted from Ref [128]. MDPI Open Access 2019).

Figure 4

Cryo-TEM image of multicompartment cubosome particles loaded with the neurotrophic protein BDNF. (Reprinted with permission from Ref [144]. Copyright 2020 American Chemical Society) BDNF is a water-soluble protein, which interacts with the lipid bilayer, changes the membrane curvature, and induces multiphase domains within the self-assembled lipid membrane particles. L—denotes lamellar phase domain, D—double diamond type cubic phase domain, and G—gyroid type cubic phase domain.

Figure 5

Tumor-bearing brain accumulation of ANG-CLP/PTX/pEGFP-hTRAIL liposomes (i.e., Angiopep-2-modified liposome assemblies loaded with pEGFP-hTRAIL and PTX were visualized by real-time in vivo fluorescence imaging of intracranial U87 MG glioma tumor-bearing nude mice after intravenous injection. (Reprinted with permission from Ref [152]. Copyright 2020 Elsevier).

Figure 6

(Top panel) Scheme of the preparation of hyaluronic acid (HA)-based hydrogels functionalized with RGD ligands for central nervous system (CNS) regeneration. (Bottom panel) 3D two-photon microscopy images of neurite outgrowth (β3 tubulin staining) at day 21 after plating hippocampal neural progenitor cells on the surface of hydrogels with a storage modulus of 400 Pa (A) or 800 Pa (B). (Reprinted with permission from Ref [153]. Copyright 2016 American Chemical Society).

Figure 7

Scheme illustrating BDNF transport by dense core vesicles and its release activating neurotrophic BDNF-TrkB signaling, which interplays with glutamate-induced excitotoxicity activities in synapses. (Reprinted from Ref [158]. Frontiers Open Access 2019).

Figure 8

Scheme of the preparation of PEGylated PAMAM-based nanoparticles containing BDNF and images showing the cellular localization of the nanoparticles in SH-SY5Y cells. The panel on the left presents the control group. The panel on the right presents the cells after 24 h of exposure to BDNF-PAMAM-AF488-PEG. The nanoparticles are observed in green, and the cells are costained with WGA-Texas Red-X (red) and DAPI (blue). (Reprinted with permission from Ref [176]. Copyright 2020 Springer Nature).

Figure 9

Strategy of BDNF delivery using pharmacologically active microcarriers (PAMs) coated with fibronectin and embedded in a hydrogel scaffold. (Reprinted with permission from Ref [171]. Copyright 2017 Elsevier).

Figure 10

Cryo-TEM images of dispersed liquid crystalline lipid nanoparticles generated by self-assembly of an omega-3 polyunsaturated fatty acid (ω-3 PUFA) and the nonlamellar lipid monoolein. The varying degree of packing and perforation of the bicontinuous lipid membrane yields different types of nano-objects, e.g., small cubosomes, cubosomal intermediates, spongosome particles, swollen sponge-type membranes coexisting with vesicular objects or objects embedding oil-rich domains. The resulting compartmentalized nanocarriers may coencapsulate hydrophobic and hydrophilic guest molecules of interest for combination therapies. (Reprinted from Ref [185]. American Chemical Society Open Access 2018).

Figure 11

Cryo-TEM images of lipid nanoparticles obtained by self-assembly of custom-synthesized plasmenyl (ether) and ester phospholipids with long PUFA (22:5 n6) chains and the nonlamellar lipid monoolein. The liquid crystalline nanoparticle topologies and the compartmentalized biomimetic supramolecular architectures comprise vesicles, cubosomal intermediates, cubosomes coexisting with vesicles, multicompartment core-shell cubosomes and hexosomes, multilayer onions; vesicles with joint oil domains, double membrane vesicles, nonlamellar intermediates with H_II domains, and dense core (H_II) particles hexosomes coexisting with vesicles. (Reprinted from Ref [190]. Frontiers Open Access 2021).