{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:45:13Z","timestamp":1785804313117,"version":"3.56.0"},"reference-count":60,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sig Transduct Target Ther"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Mitochondrial dysfunction is a primary pathogenic mechanism underlying dopaminergic neuron loss in the nigrostriatal pathway in Parkinson\u2019s disease (PD). To investigate mitochondrion-targeted therapeutic strategies, we utilized the MitoPark mouse model, in which mitochondrial transcription factor A (\n                    <jats:italic>Tfam<\/jats:italic>\n                    ) is selectively ablated in midbrain dopamine neurons, resulting in progressive neurodegeneration. We designed multifunctional lyotropic liquid crystalline nanoparticles (LCNPs) of the cubosome and hexosome types for noninvasive nose-to-brain delivery. These nanocarriers were engineered with lipids essential for membrane integrity (plasmalogens and \u03c9-3 polyunsaturated fatty acids (PUFAs)) and a nonlamellar structural lipid (monoolein). They coencapsulated the neuroprotective antioxidants ginkgolide B and quercetin. To facilitate neuronal targeting and uptake, the surface of the LCNP was modified by conjugation with pituitary adenylate cyclase-activating polypeptide (PACAP) and a rabies virus glycoprotein (RVG)-derived peptide-oleic acid (RVG-OL) conjugate. In vitro studies using differentiated SH-SY5Y cells subjected to oxidative stress demonstrated that the targeted LNPs enhanced cellular uptake and activated key neuroprotective signaling cascades, including AKT, ERK, and STAT3 phosphorylation. In vivo, intranasal administration of the optimized LNPs in MitoPark mice was associated with a trend toward the preservation of dopaminergic neuronal markers (such as tyrosine hydroxylase) and the regulation of mitochondrial-related proteins such as ATP5A1. Transcriptomic profiling revealed extensive molecular reprogramming. The peptide-functionalized LNPs upregulated genes enriched in mitochondrial biogenesis (\n                    <jats:italic>Ppargc1a<\/jats:italic>\n                    and\n                    <jats:italic>Pink1<\/jats:italic>\n                    ) and survival (\n                    <jats:italic>Bcl2<\/jats:italic>\n                    ) but downregulated the expression of neuroinflammatory mediators (\n                    <jats:italic>Il6<\/jats:italic>\n                    ,\n                    <jats:italic>Nos2, Myd88, and Trem2<\/jats:italic>\n                    ) and apoptotic effectors. These findings establish peptide-targeted, therapeutic lipid (plasmalogen\/PUFA)-based nanoassemblies as a potent nonviral platform for noninvasive nose-to-brain delivery that may modulate mitochondrial- and neurodegeneration-related signaling pathways in a genetic model of PD.\n                  <\/jats:p>","DOI":"10.1038\/s41392-026-02897-w","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:01:17Z","timestamp":1785801677000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Peptide-targeted cubosome and hexosome nanoassemblies mitigate mitochondrial dysfunction in a MitoPark model"],"prefix":"10.1038","volume":"11","author":[{"given":"Thelma","family":"Akanchise","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fucen","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Borislav","family":"Angelov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuru","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takehiko","family":"Fujino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0285-0637","authenticated-orcid":false,"given":"Angelina","family":"Angelova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"2897_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-18064-9","volume":"7","author":"WR Lee","year":"2017","unstructured":"Lee, W. R. et al. Transcriptomic analysis of mitochondrial TFAM depletion changing cell morphology and proliferation. Sci. Rep. 7, 17841 (2017).","journal-title":"Sci. Rep."},{"key":"2897_CR2","doi-asserted-by":"publisher","first-page":"3225","DOI":"10.1091\/mbc.e07-05-0404","volume":"18","author":"BA Kaufman","year":"2007","unstructured":"Kaufman, B. A. et al. The Mitochondrial Transcription Factor TFAM Coordinates the Assembly of Multiple DNA Molecules into Nucleoid-like Structures. Mol. Biol. Cell 18, 3225\u20133236 (2007).","journal-title":"Mol. Biol. Cell"},{"key":"2897_CR3","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.mito.2015.10.001","volume":"25","author":"A Picca","year":"2015","unstructured":"Picca, A. & Lezza, A. M. S. Regulation of mitochondrial biogenesis through TFAM\u2013mitochondrial DNA interactions. Mitochondrion 25, 67\u201375 (2015).","journal-title":"Mitochondrion"},{"key":"2897_CR4","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/S1474-4422(07)70327-7","volume":"7","author":"AH Schapira","year":"2008","unstructured":"Schapira, A. H. Mitochondria in the etiology and pathogenesis of Parkinson\u2019s disease. Lancet Neurol 7, 97\u2013109 (2008).","journal-title":"Lancet Neurol"},{"key":"2897_CR5","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1073\/pnas.0605208103","volume":"104","author":"MI Ekstrand","year":"2007","unstructured":"Ekstrand, M. I. et al. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc. Natl. Acad. Sci. 104, 1325\u20131330 (2007).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"2897_CR6","doi-asserted-by":"publisher","first-page":"S185","DOI":"10.1016\/S1353-8020(09)70811-9","volume":"15","author":"MI Ekstrand","year":"2009","unstructured":"Ekstrand, M. I. & Galter, D. The MitoPark Mouse \u2013 An animal model of Parkinson\u2019s disease with impaired respiratory chain function in dopamine neurons. Parkinsonism Relat. Disord. 15, S185\u2013S188 (2009).","journal-title":"Parkinsonism Relat. Disord."},{"key":"2897_CR7","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1111\/j.1601-183X.2009.00542.x","volume":"9","author":"D Galter","year":"2010","unstructured":"Galter, D. et al. MitoPark mice mirror the slow progression of key symptoms and L-DOPA response in Parkinson\u2019s disease. Genes Brain Behav 9, 173\u2013181 (2010).","journal-title":"Genes Brain Behav"},{"key":"2897_CR8","doi-asserted-by":"publisher","first-page":"e71341","DOI":"10.1371\/journal.pone.0071341","volume":"8","author":"X Li","year":"2013","unstructured":"Li, X. et al. Cognitive Dysfunction Precedes the Onset of Motor Symptoms in the MitoPark Mouse Model of Parkinson\u2019s Disease. PLoS ONE 8, e71341 (2013).","journal-title":"PLoS ONE"},{"key":"2897_CR9","doi-asserted-by":"publisher","first-page":"113707","DOI":"10.1016\/j.expneurol.2021.113707","volume":"341","author":"MJ Beckstead","year":"2021","unstructured":"Beckstead, M. J. & Howell, R. D. Progressive parkinsonism due to mitochondrial impairment: Lessons from the MitoPark mouse model. Exp. Neurol. 341, 113707 (2021).","journal-title":"Exp. Neurol."},{"key":"2897_CR10","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1089\/ars.2016.6905","volume":"27","author":"M Langley","year":"2017","unstructured":"Langley, M. et al. Mito-Apocynin Prevents Mitochondrial Dysfunction, Microglial Activation, Oxidative Damage, and Progressive Neurodegeneration in MitoPark Transgenic Mice. Antioxid. Redox Signal. 27, 1048\u20131066 (2017).","journal-title":"Antioxid. Redox Signal."},{"key":"2897_CR11","doi-asserted-by":"publisher","first-page":"1356703","DOI":"10.3389\/fnins.2024.1356703","volume":"18","author":"M Ay","year":"2024","unstructured":"Ay, M. et al. Mito-metformin protects against mitochondrial dysfunction and dopaminergic neuronal degeneration by activating upstream PKD1 signaling in cell culture and MitoPark animal models of Parkinson\u2019s disease. Front. Neurosci. 18, 1356703 (2024).","journal-title":"Front. Neurosci."},{"key":"2897_CR12","doi-asserted-by":"publisher","first-page":"1904","DOI":"10.3390\/pharmaceutics13111904","volume":"13","author":"F Maigler","year":"2021","unstructured":"Maigler, F. et al. Selective CNS Targeting and Distribution with a Refined Region-Specific Intranasal Delivery Technique via the Olfactory Mucosa. Pharmaceutics 13, 1904 (2021).","journal-title":"Pharmaceutics"},{"key":"2897_CR13","doi-asserted-by":"publisher","first-page":"393","DOI":"10.3390\/antiox12020393","volume":"12","author":"T Akanchise","year":"2023","unstructured":"Akanchise, T. & Angelova, A. Potential of Nano-Antioxidants and Nanomedicine for Recovery from Neurological Disorders Linked to Long COVID Syndrome. Antioxidants 12, 393 (2023).","journal-title":"Antioxidants"},{"key":"2897_CR14","doi-asserted-by":"publisher","first-page":"e29680","DOI":"10.1002\/jmv.29680","volume":"96","author":"T Akanchise","year":"2024","unstructured":"Akanchise, T., Angelov, B. & Angelova, A. Nanomedicine-mediated recovery of antioxidant glutathione peroxidase activity after oxidative-stress cellular damage: Insights for neurological long COVID. J. Med. Virol. 96, e29680 (2024).","journal-title":"J. Med. Virol."},{"key":"2897_CR15","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.ebiom.2017.02.012","volume":"17","author":"T Fujino","year":"2017","unstructured":"Fujino, T. et al. Efficacy and Blood Plasmalogen Changes by Oral Administration of Plasmalogen in Patients with Mild Alzheimer\u2019s Disease and Mild Cognitive Impairment: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial. eBioMedicine 17, 199\u2013205 (2017).","journal-title":"eBioMedicine"},{"key":"2897_CR16","doi-asserted-by":"publisher","first-page":"1230","DOI":"10.1002\/ptr.6887","volume":"35","author":"G Derosa","year":"2021","unstructured":"Derosa, G., Maffioli, P., D\u2019Angelo, A. & Di Pierro, F. A role for quercetin in coronavirus disease 2019 (COVID-19). Phytother. Res. 35, 1230\u20131236 (2021).","journal-title":"Phytother. Res."},{"key":"2897_CR17","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1016\/j.clnu.2011.01.010","volume":"30","author":"AW Boots","year":"2011","unstructured":"Boots, A. W., Drent, M., de Boer, V. C. J., Bast, A. & Haenen, G. R. M. M. Quercetin reduces markers of oxidative stress and inflammation in sarcoidosis. Clin. Nutr. 30, 506\u2013512 (2011).","journal-title":"Clin. Nutr."},{"key":"2897_CR18","doi-asserted-by":"publisher","first-page":"525","DOI":"10.3390\/antiox11030525","volume":"11","author":"SM Barbalho","year":"2022","unstructured":"Barbalho, S. M. et al. Ginkgo biloba in the Aging Process: A Narrative Review. Antioxidants 11, 525 (2022).","journal-title":"Antioxidants"},{"key":"2897_CR19","doi-asserted-by":"publisher","first-page":"5689","DOI":"10.1007\/s11033-021-06535-2","volume":"48","author":"M Gachowska","year":"2021","unstructured":"Gachowska, M., Szlasa, W., Saczko, J. & Kulbacka, J. Neuroregulatory role of ginkgolides. Mol. Biol. Rep. 48, 5689\u20135697 (2021).","journal-title":"Mol. Biol. Rep."},{"key":"2897_CR20","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.ejphar.2010.08.002","volume":"647","author":"Q Xiao","year":"2010","unstructured":"Xiao, Q. et al. Ginkgolide B protects hippocampal neurons from apoptosis induced by beta-amyloid 25\u201335 partly via upregulation of brain-derived neurotrophic factor. Eur. J. Pharmacol. 647, 48\u201354 (2010).","journal-title":"Eur. J. Pharmacol."},{"key":"2897_CR21","doi-asserted-by":"publisher","first-page":"1562","DOI":"10.3390\/pharmaceutics15051562","volume":"15","author":"T Akanchise","year":"2023","unstructured":"Akanchise, T. & Angelova, A. Ginkgo Biloba and Long COVID: In Vivo and In Vitro Models for the Evaluation of Nanotherapeutic Efficacy. Pharmaceutics 15, 1562 (2023).","journal-title":"Pharmaceutics"},{"key":"2897_CR22","doi-asserted-by":"publisher","first-page":"408","DOI":"10.3390\/antiox11020408","volume":"11","author":"A Ashok","year":"2022","unstructured":"Ashok, A. et al. Antioxidant Therapy in Oxidative Stress-Induced Neurodegenerative Diseases: Role of Nanoparticle-Based Drug Delivery Systems in Clinical Translation. Antioxidants 11, 408 (2022).","journal-title":"Antioxidants"},{"key":"2897_CR23","doi-asserted-by":"publisher","first-page":"3008","DOI":"10.1039\/C8FO00643A","volume":"9","author":"H Che","year":"2018","unstructured":"Che, H. et al. A comparative study of EPA-enriched ethanolamine plasmalogen and EPA-enriched phosphatidylethanolamine on A\u03b242 induced cognitive deficiency in a rat model of Alzheimer\u2019s disease. Food Funct 9, 3008\u20133017 (2018).","journal-title":"Food Funct"},{"key":"2897_CR24","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.brainresbull.2022.06.002","volume":"186","author":"T-X Yang","year":"2022","unstructured":"Yang, T.-X. et al. EPA-enriched plasmalogen attenuates the cytotoxic effects of LPS-stimulated microglia on the SH-SY5Y neuronal cell line. Brain Res. Bull. 186, 143\u2013152 (2022).","journal-title":"Brain Res. Bull."},{"key":"2897_CR25","doi-asserted-by":"publisher","first-page":"9473","DOI":"10.1016\/j.biomaterials.2010.08.030","volume":"31","author":"H-H Shen","year":"2010","unstructured":"Shen, H.-H. et al. The influence of dipalmitoyl phosphatidylserine on phase behavior of and cellular response to lyotropic liquid crystalline dispersions. Biomaterials 31, 9473\u20139481 (2010).","journal-title":"Biomaterials"},{"key":"2897_CR26","doi-asserted-by":"publisher","first-page":"3132","DOI":"10.1021\/acs.molpharmaceut.1c00366","volume":"18","author":"AR Clementino","year":"2021","unstructured":"Clementino, A. R. et al. Structure and Fate of Nanoparticles Designed for the Nasal Delivery of Poorly Soluble Drugs. Mol. Pharm. 18, 3132\u20133146 (2021).","journal-title":"Mol. Pharm."},{"key":"2897_CR27","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1038\/s42004-023-01043-9","volume":"6","author":"Y Wu","year":"2023","unstructured":"Wu, Y. et al. Sustained CREB phosphorylation by lipid-peptide liquid crystalline nanoassemblies. Commun. Chem. 6, 241 (2023).","journal-title":"Commun. Chem."},{"key":"2897_CR28","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1016\/j.ijpharm.2005.11.033","volume":"309","author":"BJ Boyd","year":"2006","unstructured":"Boyd, B. J., Whittaker, D. V., Khoo, S.-M. & Davey, G. Lyotropic liquid crystalline phases formed from glycerate surfactants as sustained release drug delivery systems. Int. J. Pharm. 309, 218\u2013226 (2006).","journal-title":"Int. J. Pharm."},{"key":"2897_CR29","doi-asserted-by":"publisher","first-page":"1731","DOI":"10.3390\/pharmaceutics14081731","volume":"14","author":"Q Wang","year":"2022","unstructured":"Wang, Q. et al. Efficient Sustained-Release Nanoparticle Delivery System Protects Nigral Neurons in a Toxin Model of Parkinson\u2019s Disease. Pharmaceutics 14, 1731 (2022).","journal-title":"Pharmaceutics"},{"key":"2897_CR30","doi-asserted-by":"publisher","first-page":"3164","DOI":"10.1021\/acsanm.8b00338","volume":"1","author":"N Kongkatigumjorn","year":"2018","unstructured":"Kongkatigumjorn, N. et al. Controlling Endosomal Escape Using pH-Responsive Nanoparticles with Tunable Disassembly. ACS Appl. Nano Mater. 1, 3164\u20133173 (2018).","journal-title":"ACS Appl. Nano Mater."},{"key":"2897_CR31","doi-asserted-by":"publisher","first-page":"139420","DOI":"10.1016\/j.jcis.2025.139420","volume":"704","author":"T Akanchise","year":"2026","unstructured":"Akanchise, T. et al. Rapid structural transformation of ionizable lipid nanoparticles involving Omega-3 polyunsaturated fatty acids enhances antioxidant defense and mitochondrial proteins activity in pH-responsive drug delivery. J. Colloid Interface Sci. 704, 139420 (2026).","journal-title":"J. Colloid Interface Sci."},{"key":"2897_CR32","doi-asserted-by":"publisher","first-page":"299","DOI":"10.2147\/IJN.S347187","volume":"17","author":"S Fakhri","year":"2022","unstructured":"Fakhri, S. et al. Nanoparticles in Combating Neuronal Dysregulated Signaling Pathways: Recent Approaches to the Nanoformulations of Phytochemicals and Synthetic Drugs Against Neurodegenerative Diseases. Int. J. Nanomedicine 17, 299\u2013331 (2022).","journal-title":"Int. J. Nanomedicine"},{"key":"2897_CR33","doi-asserted-by":"publisher","first-page":"1658","DOI":"10.1021\/acschemneuro.6b00207","volume":"7","author":"P Kundu","year":"2016","unstructured":"Kundu, P., Das, M., Tripathy, K. & Sahoo, S. K. Delivery of Dual Drug Loaded Lipid Based Nanoparticles across the Blood\u2013Brain Barrier Impart Enhanced Neuroprotection in a Rotenone Induced Mouse Model of Parkinson\u2019s Disease. ACS Chem. Neurosci. 7, 1658\u20131670 (2016).","journal-title":"ACS Chem. Neurosci."},{"key":"2897_CR34","doi-asserted-by":"publisher","first-page":"8391","DOI":"10.3390\/ijms24098391","volume":"24","author":"SC Badoiu","year":"2023","unstructured":"Badoiu, S. C. et al. PI3K\/AKT\/mTOR Dysregulation and Reprogramming Metabolic Pathways in Renal Cancer: Crosstalk with the VHL\/HIF Axis. Int. J. Mol. Sci. 24, 8391 (2023).","journal-title":"Int. J. Mol. Sci."},{"key":"2897_CR35","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1021\/bm401906p","volume":"15","author":"Y Gao","year":"2014","unstructured":"Gao, Y. et al. RVG-Peptide-Linked Trimethylated Chitosan for Delivery of siRNA to the Brain. Biomacromolecules 15, 1010\u20131018 (2014).","journal-title":"Biomacromolecules"},{"key":"2897_CR36","doi-asserted-by":"publisher","first-page":"148691","DOI":"10.1016\/j.brainres.2023.148691","volume":"1824","author":"RD Smit","year":"2024","unstructured":"Smit, R. D. et al. STAT3 protects dopaminergic neurons against degeneration in animal model of Parkinson\u2019s disease. Brain Res 1824, 148691 (2024).","journal-title":"Brain Res"},{"key":"2897_CR37","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1016\/j.bbrc.2009.05.051","volume":"385","author":"SP Barry","year":"2009","unstructured":"Barry, S. P. et al. STAT3 deletion sensitizes cells to oxidative stress. Biochem. Biophys. Res. Commun. 385, 324\u2013329 (2009).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2897_CR38","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-15342-4","volume":"7","author":"X Cheng","year":"2017","unstructured":"Cheng, X., Peuckert, C. & W\u00f6lfl, S. Essential role of mitochondrial Stat3 in p38MAPK mediated apoptosis under oxidative stress. Sci. Rep. 7, 15388 (2017).","journal-title":"Sci. Rep."},{"key":"2897_CR39","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2202-9-S3-S5","volume":"9","author":"LR Hanson","year":"2008","unstructured":"Hanson, L. R. & Frey, W. H. Intranasal delivery bypasses the blood\u2012brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci 9, S5 (2008).","journal-title":"BMC Neurosci"},{"key":"2897_CR40","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1016\/j.jconrel.2023.06.026","volume":"360","author":"EF Van Vliet","year":"2023","unstructured":"Van Vliet, E. F., Knol, M. J., Schiffelers, R. M., Caiazzo, M. & Fens, M. H. A. M. Levodopa-loaded nanoparticles for the treatment of Parkinson\u2019s disease. J. Controlled Release 360, 212\u2013224 (2023).","journal-title":"J. Controlled Release"},{"key":"2897_CR41","doi-asserted-by":"publisher","first-page":"69103","DOI":"10.1021\/acsami.4c18679","volume":"16","author":"V Di Francesco","year":"2024","unstructured":"Di Francesco, V., Chua, A. J., Bleier, B. S. & Amiji, M. M. Effective Nose-to-Brain Delivery of Blood-Brain Barrier Impermeant Anti-IL-1\u03b2 Antibody via the Minimally Invasive Nasal Depot (MIND) Technique. ACS Appl. Mater. Interfaces 16, 69103\u201369113 (2024).","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"2897_CR42","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1007\/s00401-017-1792-9","volume":"135","author":"NL Rey","year":"2018","unstructured":"Rey, N. L. et al. Spread of aggregates after olfactory bulb injection of \u03b1-synuclein fibrils is associated with early neuronal loss and is reduced long term. Acta Neuropathol. (Berl.) 135, 65\u201383 (2018).","journal-title":"Acta Neuropathol. (Berl.)"},{"key":"2897_CR43","first-page":"612","volume":"17","author":"E Asimakidou","year":"2024","unstructured":"Asimakidou, E., Tan, J. K. S., Zeng, J. & Lo, C. H. Blood\u2012Brain Barrier-Targeting Nanoparticles: Biomaterial Properties and Biomedical Applications in Translational Neuroscience. Pharm. Basel Switz. 17, 612 (2024).","journal-title":"Pharm. Basel Switz."},{"key":"2897_CR44","doi-asserted-by":"publisher","first-page":"58","DOI":"10.3390\/pharmaceutics16010058","volume":"16","author":"S Dighe","year":"2023","unstructured":"Dighe, S., Jog, S., Momin, M., Sawarkar, S. & Omri, A. Intranasal Drug Delivery by Nanotechnology: Advances in and Challenges for Alzheimer\u2019s Disease Management. Pharmaceutics 16, 58 (2023).","journal-title":"Pharmaceutics"},{"key":"2897_CR45","doi-asserted-by":"publisher","first-page":"4153","DOI":"10.3390\/ijms23084153","volume":"23","author":"AM Hersh","year":"2022","unstructured":"Hersh, A. M., Alomari, S. & Tyler, B. M. Crossing the Blood\u2012Brain Barrier: Advances in Nanoparticle Technology for Drug Delivery in Neuro-Oncology. Int. J. Mol. Sci. 23, 4153 (2022).","journal-title":"Int. J. Mol. Sci."},{"key":"2897_CR46","doi-asserted-by":"publisher","DOI":"10.1186\/s12951-025-03415-w","volume":"23","author":"S Liu","year":"2025","unstructured":"Liu, S. et al. Advances in brain-targeted delivery strategies and natural product-mediated enhancement of blood\u2013brain barrier permeability. J. Nanobiotechnology 23, 382 (2025).","journal-title":"J. Nanobiotechnology"},{"key":"2897_CR47","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1039\/D1TB02015C","volume":"10","author":"Q Meng","year":"2022","unstructured":"Meng, Q. et al. Influence of nanoparticle size on blood\u2013brain barrier penetration and the accumulation of anti-seizure medicines in the brain. J. Mater. Chem. B 10, 271\u2013281 (2022).","journal-title":"J. Mater. Chem. B"},{"key":"2897_CR48","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1016\/j.molmed.2015.06.001","volume":"21","author":"DM O\u2019Connor","year":"2015","unstructured":"O\u2019Connor, D. M. & Boulis, N. M. Gene therapy for neurodegenerative diseases. Trends Mol. Med. 21, 504\u2013512 (2015).","journal-title":"Trends Mol. Med."},{"key":"2897_CR49","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1038\/nmeth.1226","volume":"5","author":"A Mortazavi","year":"2008","unstructured":"Mortazavi, A., Williams, B. A., McCue, K., Schaeffer, L. & Wold, B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat. Methods 5, 621\u2013628 (2008).","journal-title":"Nat. Methods"},{"key":"2897_CR50","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/nrg2484","volume":"10","author":"Z Wang","year":"2009","unstructured":"Wang, Z., Gerstein, M. & Snyder, M. RNA-Seq: a revolutionary tool for transcriptomics. Nat. Rev. Genet. 10, 57\u201363 (2009).","journal-title":"Nat. Rev. Genet."},{"key":"2897_CR51","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1093\/bioinformatics\/btu684","volume":"31","author":"G Yu","year":"2015","unstructured":"Yu, G., Wang, L.-G., Yan, G.-R. & He, Q.-Y. DOSE: an R\/Bioconductor package for disease ontology semantic and enrichment analysis. Bioinformatics 31, 608\u2013609 (2015).","journal-title":"Bioinformatics"},{"key":"2897_CR52","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/omi.2011.0118","volume":"16","author":"G Yu","year":"2012","unstructured":"Yu, G., Wang, L.-G., Han, Y. & He, Q.-Y. clusterProfiler: an R Package for Comparing Biological Themes Among Gene Clusters. OMICS J. Integr. Biol. 16, 284\u2013287 (2012).","journal-title":"OMICS J. Integr. Biol."},{"key":"2897_CR53","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1038\/nbt.3122","volume":"33","author":"M Pertea","year":"2015","unstructured":"Pertea, M. et al. StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat. Biotechnol. 33, 290\u2013295 (2015).","journal-title":"Nat. Biotechnol."},{"key":"2897_CR54","doi-asserted-by":"crossref","unstructured":"Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, (2014).","DOI":"10.1186\/s13059-014-0550-8"},{"key":"2897_CR55","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","volume":"30","author":"Y Liao","year":"2014","unstructured":"Liao, Y., Smyth, G. K. & Shi, W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30, 923\u2013930 (2014).","journal-title":"Bioinformatics"},{"key":"2897_CR56","doi-asserted-by":"crossref","unstructured":"Young, M. D., Wakefield, M. J., Smyth, G. K. & Oshlack, A. Gene ontology analysis for RNA-seq: accounting for selection bias. Genome Biol. 11, (2010).","DOI":"10.1186\/gb-2010-11-2-r14"},{"key":"2897_CR57","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.jip.2017.12.002","volume":"151","author":"Z He","year":"2018","unstructured":"He, Z. et al. Comparative transcriptome and gene coexpression network analysis reveal genes and signaling pathways adaptively responsive to varied adverse stresses in the insect fungal pathogen, Beauveria bassiana. J. Invertebr. Pathol. 151, 169\u2013181 (2018).","journal-title":"J. Invertebr. Pathol."},{"key":"2897_CR58","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1101\/gr.107524.110","volume":"20","author":"A McKenna","year":"2010","unstructured":"McKenna, A. et al. The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20, 1297\u20131303 (2010).","journal-title":"Genome Res"},{"key":"2897_CR59","doi-asserted-by":"crossref","unstructured":"Shen, S. et al. rMATS: Robust and flexible detection of differential alternative splicing from replicate RNA-Seq data. Proc. Natl. Acad. Sci. 111, (2014).","DOI":"10.1073\/pnas.1419161111"},{"key":"2897_CR60","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1002\/gene.10023","volume":"32","author":"DR Shimshek","year":"2002","unstructured":"Shimshek, D. R. et al. Codon-improved Cre recombinase (iCre) expression in the mouse. Genesis 32, 19\u201326 (2002).","journal-title":"Genesis"}],"container-title":["Signal Transduction and Targeted Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41392-026-02897-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41392-026-02897-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41392-026-02897-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:01:19Z","timestamp":1785801679000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41392-026-02897-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,4]]},"references-count":60,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["2897"],"URL":"https:\/\/doi.org\/10.1038\/s41392-026-02897-w","relation":{},"ISSN":["2059-3635"],"issn-type":[{"value":"2059-3635","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,4]]},"assertion":[{"value":"27 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 April 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 June 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 August 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"310"}}