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• W4214722279 abstract "NanomedicineVol. 17, No. 8 EditorialOpen AccessSelective targeting of neurons using nanomedicine-based strategies: open questions and new opportunitiesRosalia Rodriguez-Rodriguez & Sabina QuaderRosalia Rodriguez-Rodriguez **Author for correspondence: Tel.: +34 935 042 002; E-mail Address: rrodriguez@uic.eshttps://orcid.org/0000-0002-6908-7197Basic Sciences Department, Faculty of Medicine & Health Sciences, Universitat Internacional de Catalunya, Sant Cugat del Vallès, 08195, SpainSearch for more papers by this author & Sabina Quader *Author for correspondence: Tel.: +81 445 895 920; E-mail Address: sabina-q@kawasaki-net.ne.jphttps://orcid.org/0000-0002-9616-7408Innovation Center of Nanomedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Kanagawa, 210-0821, JapanSearch for more papers by this authorPublished Online:28 Feb 2022https://doi.org/10.2217/nnm-2021-0486AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInReddit Keywords: gene/drug deliverynanoparticlesneuron-related diseasesneuron targetingNeuron-related disorders have a significant impact on our society. These disorders include a wide range of pathologies with neuronal disruption such as neurodegenerative diseases (e.g., Alzheimer's and Parkinson's) and metabolic diseases that are strictly regulated by neuronal connections (e.g., insulin resistance and obesity). However, investigation of the pathophysiology and pharmacological treatment of these disorders is limited due to the difficulty of targeting specific populations of neurons, low bioavailability in the brain and side effects of the drugs by off-target actions.Nanotechnology-based treatment approaches (or nanomedicines) address many of these limitations, thus offering better therapeutic outcomes. Several nanomedicines have been developed to improve the pharmacokinetics and biodistribution of drugs or any other type of cargo relative to the free form within the CNS; only a few of these are designed to target neurons. Despite the advances that nanomedicines offer in reaching brain cells and treating neuron-related diseases, there are still relevant open questions that need further exploration: which is the best targeting strategy (e.g., surface decoration with neuron-targeting ligands or playing with surface charges)? Do the inherent structural features of nanomedicines have any impact on neuron targetability when compared with other types of brain cells (e.g., inorganic, polymeric or exosome-based nanomedicines)? How exactly are the nanomedicines interacting with neurons and is the targeting related to the excitability and activity of neurons compared with non-excitable brain cells? Is it possible to specifically stimulate neurons with specially designed nanomedicines to facilitate uptake that can eventually improve specific neuronal delivery? In terms of in vivo delivery, what are the true benefits of nose-to-brain delivery compared with other types of administration routes for targeting neurons? Answering and exploring these issues are of crucial importance to clarify the role of nanomedicines as a viable therapy option for neuron-related diseases and the understanding of the molecular mechanisms and neuronal circuitries underlying these pathologies.It is worth noting that most nanomedicines targeting neuronal diseases have been developed to deliver therapies in Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy and amyotrophic lateral sclerosis (ALS). These strategies are primarily polymeric nanomedicines encapsulating drugs (e.g., levodopa, memantine) or mRNA (e.g., anti-SNCA), which can reach neurons or the vicinity of brain cells in pre-clinical models [1]. These formulations increase cargo availability in the brain and the effectiveness of the therapy in disease models by including ligands or controlling glucose density on the surface for improved blood–brain barrier (BBB) crossing when administered systemically [2–4]. Alternatively, nanomedicines are prepared for the effective targeting of brain cells via nose-to-brain delivery of anti-epileptic drugs [5]. Most of these nanomedicines consist of passive neuron targeting; although they can be clinically relevant in improving the drug's access to the brain, they still rely on the ability of other brain cells to non-specifically internalize the drug or the nanocarrier, leading to undesired effects and lower therapeutic efficiency. To overcome this problem, there are some promising nanomedicines using active approaches with specific ligands on the surface that increase the internalization in neurons. For instance, surface decoration with Tet1, a peptide that binds specifically to neurons, in addition to peptides aiding BBB crossing, has allowed polymeric nanoparticles to deliver siRNA and drugs effectively in AD mice models, with promising results in cognitive function [6,7]. It is also important to highlight the elegant nanoformulation proposed by Yang et al. [8], using neuronal mitochondria-targeted PEG-PLA-based nanocarriers co-decorated with peptide C3 and triphenylphosphonium (TPP) to reach both hippocampal neurons and neuronal mitochondria, respectively, then delivering the drug, resveratrol, and attenuating oxidative damage in the mitochondria of impaired neurons in AD models. Although these laboratory studies show exciting outcomes, the number of nanoformulations used in humans treating neurodegenerative disorders remains low, and current treatments do not demonstrate specific brain cell targeting. Therefore, the progression and development of nanomedicine-based approaches, particularly those using active targeting at the pre-clinical stage, will be crucial in establishing clinical relevance in neuron-related disorders in humans.The improvements and applications that neuron-targeted nanomedicines offer go beyond the treatment of neurodegenerative diseases such as AD and PD. For instance, modulation of lipid sensing and metabolism in hypothalamic neurons has been strongly related to the regulation of energy homeostasis [9,10]. Modulation of these processes in these neurons may therefore be a promising strategy for treating obesity and associated pathologies, such as type 2 diabetes [9–11]. Since the current approaches to combating obesity and its complications have limited clinical effectiveness, selective targeting of brain cells to regulate energy balance using nanotechnology seems a very encouraging strategy to prevent metabolic disruption of peripheral tissues and to treat this unaddressed medical issue without off-target effects. A remarkable study led by Milbank et al. [12] used a blood-to-brain delivery system consisting of genetically designed small extracellular vesicles (SEVs) that contained plasmid DNA encoding an AMPKα1 dominant-negative mutant (AMPKα1-DN) with the intention of reducing the production of the cellular energy sensor AMPKα1 selectively in SF1 neurons in the ventromedial hypothalamus of mice with diet-induced obesity. Intravenous administration of these SEVs induced a rapid and sustained loss of body weight by reducing adiposity and activation of brown fat thermogenesis without changes in food intake. Modulation of proteins involved in lipid metabolism of hypothalamic neurons, such as CPT1A, may also be an important strategy against obesity. The study by Paraiso et al. [13] used poly–ion complex micelles to deliver the specific CPT1A inhibitor, C75-CoA, into hypothalamic neurons. The micelles encapsulating C75-CoA resulted in up to a fivefold reduction of ATP synthesis and fatty acid oxidation inhibition in neurons compared with free drugs. Also, the nanoparticle showed significantly higher uptake and internalization in neuronal cell lines and spheroids than the free CPT1A inhibitor. The positive results of the micelle compared with the free drug suggest the promising effects of these nanoformulations in modifying neuronal lipid metabolism in specific neurons of the hypothalamus in vivo and regulating energy homeostasis. Both of these studies are recent examples of using nanotechnology for the selective delivery of a therapeutic to brain cells, extending the strategy to potential applications in treating obesity, associated comorbidities and other diseases or conditions with a brain component.In addition to targeting neuronal proteins and the type of surface ligands for neuronal targeting, other nanomaterial-related properties are a crucial matter for study in the field. For instance, the negative charges on the surface of inorganic nanoparticles provide selective uptake and interaction with neurons but not with other brain cells in co-cultures of primary cells [14] and rat brain slices [15]. The charge, but no other nanomaterial properties (e.g., shape), is involved in this neuronal interaction. Interestingly, Dante et al. [14] also suggest that the interaction of the inorganic nanoparticles with neurons is based on these cells' excitability properties compared with other brain cells. The importance of the surface charge was also evaluated by Musumeci et al. when using rhodamine B-loaded polymeric nanoparticles for intranasal administration in rats [16], indicating that surface charge affects the localization of the fluorescence in the brain. Specifically, the positive charge slows down the progress of the nanoparticles to the brain due to the involvement of the trigeminal pathway, whereas the olfactory pathway may be responsible for the transport of negatively charged nanoparticles, and systemic pathways cannot be excluded.The recently reported polymeric nanoparticle neuronal tracers (NNTs) [17] represent a new type of potential targeted drug carrier to selective neurons. The authors reported a set of multicolor fluorescent NNTs obtained through emulsion polymerization and showed their retrograde transport performance in mice in vivo [17]. Neuronal tracers were injected into a brain region, and then they were locally taken up by neurons and transported in a retrograde fashion (from axon to soma), mapping the anatomical connections in the brain and providing information about neuronal function and pathology. The conjugation of a therapeutic cargo or a contrast agent to the polymeric NNT and its injection into an upstream neuron projection would allow delivery of the cargo in a retrograde direction to a specific neuron population in the brain [17].Altogether, nanomedicines are showing significant potential to effectively deliver therapeutics to the brain, indicating promising outcomes in treating neuron-related diseases. However, it is also essential to acknowledge the enormous gap between the bench and the bedside, and to identify the limitations of the current strategies. For CNS diseases, so far, the BBB has been highlighted as the primary barrier; however, the pharmacokinetic/pharmacodynamic profile of therapeutics (free or nanoformulations) within the brain is also a critical factor in the successful targeting of specific brain areas or cells. Specifically, for nanoformulations, it is also vital to evaluate the actual quantity of encapsulated drugs that is accessible and active toward targeted CNS diseases. It is also essential to pinpoint the pros and cons of the existing nanomedicine-based surface-decoration strategies and to optimize accordingly, perhaps via combination (i.e., charge and ligand). This will significantly improve the future translation of nanomedicine into the clinic for neuron-related pathologies. Finally, it is crucial to continue identifying new targets in specific brain areas/cells by studying neuronal circuits and mechanisms underlying neurodegenerative disorders and other prevalent diseases or conditions with a brain component, such as obesity and type 2 diabetes, and to combine this knowledge with nanotechnology research to formulate optimized nanotherapeutics toward effective treatments of these brain-related diseases.Financial & competing interests disclosureR Rodriguez-Rodriguez and S Quader acknowledge the Joint Bilateral Project Japan-Spain (PCI2018-092997/AEI Agencia Estatal de Investigación to R Rodriguez-Rodriguez and 20jm0210059h0003/AMED and JPJSBP120209938/JSPS to S Quader). R Rodriguez-Rodriguez also acknowledges the Spanish Ministerio de Ciencia e Innovación (ref. PID2020-114953RB-C22 by MCIN/AEI/10.13039/501100011033). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/.References1. Garcia-Chica J, Paraiso WKD, Tanabe S et al. An overview of nanomedicines for neuron targeting. Nanomedicine (Lond.) 15(16), 1617–1636 (2020).Link, CAS, Google Scholar2. Liu Z, Gao X, Kang T et al. B6 peptide-modified PEG-PLA nanoparticles for enhanced brain delivery of neuroprotective peptide. Bioconjug. Chem. 24(6), 997–1007 (2013).Crossref, Medline, CAS, Google Scholar3. Min HS, Kim HJ, Naito M et al. Systemic brain delivery of antisense oligonucleotides across the blood–brain barrier with a glucose-installed polymeric nanocarrier. Angew Chem. Int. Ed. 59(21), 8173–8180 (2020).Crossref, Medline, CAS, Google Scholar4. Anraku Y, Kuwahara H, Fukusato Y et al. Glycaemic control boosts glucosylated nanocarrier crossing the BBB into the brain. Nat. Commun. 8(1), 1001 (2017).Crossref, Medline, CAS, Google Scholar5. Musumeci T, Serapide MF, Pellitteri R et al. Oxcarbazepine free or loaded PLGA nanoparticles as effective intranasal approach to control epileptic seizures in rodents. Eur. J. Pharm. Biopharm. 133, 309–320 (2018).Crossref, Medline, CAS, Google Scholar6. Guo Q, Xu S, Yang P et al. A dual-ligand fusion peptide improves the brain-neuron targeting of nanocarriers in Alzheimer's disease mice. J. Control. Release 320, 347–362 (2020).Crossref, Medline, CAS, Google Scholar7. Wang P, Zheng X, Guo Q et al. Systemic delivery of BACE1 siRNA through neuron-targeted nanocomplexes for treatment of Alzheimer's disease. J. Control. Release 279, 220–233 (2018).Crossref, Medline, CAS, Google Scholar8. Yang P, Sheng D, Guo Q et al. Neuronal mitochondria-targeted micelles relieving oxidative stress for delayed progression of Alzheimer's disease. Biomaterials 238, 119844 (2020).Crossref, Medline, CAS, Google Scholar9. Casals N, Zammit V, Herrero L, Fado R, Rodriguez-Rodriguez R, Serra D. Carnitine palmitoyltransferase 1C: from cognition to cancer. Prog. Lipid Res. 61, 134–148 (2016).Crossref, Medline, CAS, Google Scholar10. Fadó R, Rodríguez-Rodríguez R, Casals N. The return of malonyl-CoA to the brain: cognition and other stories. Prog. Lipid Res. 81, 101071 (2021).Crossref, Medline, CAS, Google Scholar11. Fosch A, Zagmutt S, Casals N, Rodríguez-Rodríguez R. New insights of SF1 neurons in hypothalamic regulation of obesity and diabetes. Int. J. Mol. Sci. 22(12), 6186 (2021).Crossref, Medline, CAS, Google Scholar12. Milbank E, Dragano NRV, González-García I et al. Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation. Nat. Metab. 3(10), 1415–1431 (2021).Crossref, Medline, CAS, Google Scholar13. Paraiso WKD, Garcia-Chica J, Ariza X et al. Poly–ion complex micelles effectively deliver CoA-conjugated CPT1A inhibitors to modulate lipid metabolism in brain cells. Biomater. Sci. 9(21), 7076–7091 (2021).Crossref, Medline, CAS, Google Scholar14. Dante S, Petrelli A, Petrini EM et al. Selective targeting of neurons with inorganic nanoparticles: revealing the crucial role of nanoparticle surface charge. ACS Nano 11(7), 6630–6640 (2017).Crossref, Medline, CAS, Google Scholar15. Walters R, Kraig RP, Medintz I et al. Nanoparticle targeting to neurons in a rat hippocampal slice culture model. ASN Neuro 4(6), 383–392 (2012).Crossref, Medline, CAS, Google Scholar16. Bonaccorso A, Musumeci T, Serapide MF, Pellitteri R, Uchegbu IF, Puglisi G. Nose to brain delivery in rats: effect of surface charge of rhodamine B labeled nanocarriers on brain subregion localization. Colloids Surf. B Biointerfaces 154, 297–306 (2017).Crossref, Medline, CAS, Google Scholar17. Zang N, Issa JB, Ditri TB et al. Multicolor polymeric nanoparticle neuronal tracers. ACS Cent. Sci. 6(3), 436–445 (2020).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetails Vol. 17, No. 8 Follow us on social media for the latest updates Metrics History Received 28 December 2021 Accepted 1 February 2022 Published online 28 February 2022 Published in print April 2022 Information© 2022 The AuthorsKeywordsgene/drug deliverynanoparticlesneuron-related diseasesneuron targetingFinancial & competing interests disclosureR Rodriguez-Rodriguez and S Quader acknowledge the Joint Bilateral Project Japan-Spain (PCI2018-092997/AEI Agencia Estatal de Investigación to R Rodriguez-Rodriguez and 20jm0210059h0003/AMED and JPJSBP120209938/JSPS to S Quader). R Rodriguez-Rodriguez also acknowledges the Spanish Ministerio de Ciencia e Innovación (ref. PID2020-114953RB-C22 by MCIN/AEI/10.13039/501100011033). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/.PDF download" @default.
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