{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T04:47:20Z","timestamp":1785646040909,"version":"3.56.0"},"reference-count":37,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100018537","name":"National Science and Technology Major Project","doi-asserted-by":"crossref","award":["2021ZD0201005"],"award-info":[{"award-number":["2021ZD0201005"]}],"id":[{"id":"10.13039\/501100018537","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100015401","name":"Key Research and Development Projects of Shaanxi Province","doi-asserted-by":"crossref","award":["2025SF-YBXM-393"],"award-info":[{"award-number":["2025SF-YBXM-393"]}],"id":[{"id":"10.13039\/501100015401","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Key Laboratory of Neural and Vascular Biology, Ministry of Education","award":["NV20250022"],"award-info":[{"award-number":["NV20250022"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82371402"],"award-info":[{"award-number":["82371402"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82501855"],"award-info":[{"award-number":["82501855"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82371402"],"award-info":[{"award-number":["82371402"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82501855"],"award-info":[{"award-number":["82501855"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007128","name":"Natural Science Foundation of Shaanxi Province","doi-asserted-by":"crossref","award":["2025JC-YBMS-1027"],"award-info":[{"award-number":["2025JC-YBMS-1027"]}],"id":[{"id":"10.13039\/501100007128","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Autism spectrum disorder (ASD) is a group of developmental disorders featured by social dysfunction, for which there still lacks effective treatments. Our previous study demonstrated that XAV939, a tankyrase inhibitor, could alleviate social dysfunction in two ASD mouse models via suppressing Wnt and glycolytic signaling. However, its further application is limited by poor brain\u2013blood barrier penetration and low bioavailability. Methods: XAV939 was structurally optimized by esterification. The effects of XAV939-derivatives on Wnt\/glycolysis were assessed by Western blotting, Topflash luciferase assay, lactate levels and the extracellular acidification rate. Social behaviors were evaluated by a three-chamber test, a resident\u2013intruder test and ultrasonic vocalization. Biomimetic brain targeting was achieved by neuron-astrocyte hybrid cell membrane encapsulation. Periphery toxicities were examined by biochemical and histological analysis. Results: Three esterified XAV939 were synthesized. Data from both 293FT cells and primary Shank3b-\/- neurons revealed that an alkyl ester prodrug of XAV939 (named XAV939-L1) exhibited dual inhibition of Wnt\/glycolysis. Intravenous injection of XAV939-L1 effectively improved the social function of Shank3b-\/- mice but showed hepatic side effects. Further, we made brain-targeting XAV939-L1 (XAV939-L1-BT) by neuron\u2013astrocyte hybrid cell membrane encapsulation, which greatly enhanced the accumulation of XAV939-L1-BT in the brain and reduced its distribution in peripheral tissues (liver and intestine). At a half-dose of XAV939-L1, XAV939-L1-BT exhibited significant social improvement effects without obvious hepatic and intestinal toxicity. Conclusions: Our data demonstrated an esterified XAV939 and its biomimetic brain-targeted formula as a potential drug candidate for treating ASD-associated social dysfunction.<\/jats:p>","DOI":"10.3390\/pharmaceutics18080951","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T10:11:38Z","timestamp":1785492698000},"page":"951","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biomimetic Brain-Targeted Delivery of Esterified XAV939 for Treating Autism-Associated Social Deficits"],"prefix":"10.3390","volume":"18","author":[{"given":"Hanze","family":"Liu","sequence":"first","affiliation":[{"name":"Yan\u2019an Medical College, Yan\u2019an University, Yan\u2019an 716000, China"},{"name":"Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"},{"name":"The Shaanxi Province Key Laboratory of Brain Function Analysis and Modulation, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Rong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"},{"name":"The Shaanxi Province Key Laboratory of Brain Function Analysis and Modulation, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengmeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"},{"name":"The Shaanxi Province Key Laboratory of Brain Function Analysis and Modulation, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiantian","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Northwest University, No. 229, Taibai North Road, Xi\u2019an 710069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daozhou","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"},{"name":"The Shaanxi Province Key Laboratory of Brain Function Analysis and Modulation, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"},{"name":"The Shaanxi Province Key Laboratory of Brain Function Analysis and Modulation, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyiyang","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"},{"name":"The Shaanxi Province Key Laboratory of Brain Function Analysis and Modulation, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Ma","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Department of Neurobiology, Hebei Medical University, Shijiazhuang 050017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Gao","sequence":"additional","affiliation":[{"name":"Yan\u2019an Medical College, Yan\u2019an University, Yan\u2019an 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3210-9567","authenticated-orcid":false,"given":"Shengxi","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"},{"name":"The Shaanxi Province Key Laboratory of Brain Function Analysis and Modulation, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao","family":"Wei","sequence":"additional","affiliation":[{"name":"Shaanxi Key Laboratory of Chiral Drug and Vaccine Adjuvants, School of Pharmacy, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yazhou","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"},{"name":"The Shaanxi Province Key Laboratory of Brain Function Analysis and Modulation, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3194","DOI":"10.1038\/s41380-023-02201-0","article-title":"Social circuits and their dysfunction in autism spectrum disorder","volume":"28","author":"Sato","year":"2023","journal-title":"Mol. Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1001\/jamapediatrics.2014.210","article-title":"Costs of autism spectrum disorders in the United Kingdom and the United States","volume":"168","author":"Buescher","year":"2014","journal-title":"JAMA Pediatr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.pharmthera.2018.05.007","article-title":"Autism Spectrum Disorder: Classification, diagnosis and therapy","volume":"190","author":"Sharma","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1146\/annurev-publhealth-031816-044318","article-title":"The Changing Epidemiology of Autism Spectrum Disorders","volume":"38","author":"Lyall","year":"2017","journal-title":"Annu. Rev. Public Health"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Wang, L., Wang, B., Wu, C., Wang, J., and Sun, M. (2023). Autism Spectrum Disorder: Neurodevelopmental Risk Factors, Biological Mechanism, and Precision Therapy. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24031819"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1038\/s41593-019-0489-x","article-title":"A perturbed gene network containing PI3K-AKT, RAS-ERK and WNT-beta-catenin pathways in leukocytes is linked to ASD genetics and symptom severity","volume":"22","author":"Gazestani","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.pnpbp.2018.12.015","article-title":"Mitochondrial function and abnormalities implicated in the pathogenesis of ASD","volume":"92","author":"Castora","year":"2019","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"106520","DOI":"10.1016\/j.nbd.2024.106520","article-title":"Biomarkers of mitochondrial dysfunction in autism spectrum disorder: A systematic review and meta-analysis","volume":"197","author":"Frye","year":"2024","journal-title":"Neurobiol. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s00441-014-1996-4","article-title":"Wnt signalling in neuronal differentiation and development","volume":"359","author":"Inestrosa","year":"2015","journal-title":"Cell Tissue Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.conb.2010.12.002","article-title":"Wnt signaling during synaptic development and plasticity","volume":"21","author":"Budnik","year":"2011","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.brainresrev.2009.10.002","article-title":"Glucose and lactate supply to the synapse","volume":"63","author":"Barros","year":"2010","journal-title":"Brain Res. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"eadp7423","DOI":"10.1126\/sciadv.adp7423","article-title":"Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission","volume":"10","author":"Tiwari","year":"2024","journal-title":"Sci. Adv."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"129","DOI":"10.9758\/cpn.2018.16.2.129","article-title":"The Wnt Signaling Pathway and Related Therapeutic Drugs in Autism Spectrum Disorder","volume":"16","author":"Bae","year":"2018","journal-title":"Clin. Psychopharmacol. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13041-017-0343-6","article-title":"Warburg effect hypothesis in autism Spectrum disorders","volume":"11","author":"Vallee","year":"2018","journal-title":"Mol. Brain"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3749","DOI":"10.1038\/s41380-022-01627-2","article-title":"Proteomic phenotype of cerebral organoids derived from autism spectrum disorder patients reveal disrupted energy metabolism, cellular components, and biological processes","volume":"27","author":"Ilieva","year":"2022","journal-title":"Mol. Psychiatry"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e17101","DOI":"10.15252\/emmm.202217101","article-title":"Axin2 coupled excessive Wnt-glycolysis signaling mediates social defect in autism spectrum disorders","volume":"15","author":"Wang","year":"2023","journal-title":"EMBO Mol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"38353","DOI":"10.1038\/s41598-025-22327-1","article-title":"An impaired glycolysis induces ATP deficiency and reduced cell respiration in stem cells of patients with autism spectrum disorders","volume":"15","author":"Feron","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/nature09965","article-title":"Shank3 mutant mice display autistic-like behaviours and striatal dysfunction","volume":"472","author":"Peca","year":"2011","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1016\/j.cmet.2025.08.003","article-title":"Mitochondrial dysfunction reveals H(2)S-mediated synaptic sulfhydration as a potential mechanism for autism-associated social defects","volume":"37","author":"Xian","year":"2025","journal-title":"Cell Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e218","DOI":"10.1038\/emm.2015.122","article-title":"Regulation of glucose metabolism from a liver-centric perspective","volume":"48","author":"Han","year":"2016","journal-title":"Exp. Mol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1073\/pnas.2536800100","article-title":"Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1","volume":"101","author":"Kuhnert","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1038\/nature08356","article-title":"Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling","volume":"461","author":"Huang","year":"2009","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5244","DOI":"10.1021\/acs.jmedchem.1c02139","article-title":"Small-Molecule Inhibitors of Tankyrases as Prospective Therapeutics for Cancer","volume":"65","author":"Yu","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1038\/nn.2885","article-title":"Anti-TANKyrase weapons promote myelination","volume":"14","author":"Casaccia","year":"2011","journal-title":"Nat. Neurosci."},{"key":"ref_25","first-page":"538","article-title":"Advanced Engineered Nanoplatforms to Overcome Biological Barriers for Targeting Brain Tumors","volume":"26","author":"Sultana","year":"2025","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4157","DOI":"10.1007\/s00018-015-2028-6","article-title":"Canonical and noncanonical Wnt signaling in neural stem\/progenitor cells","volume":"72","author":"Kypta","year":"2015","journal-title":"Cell Mol. Life Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"106550","DOI":"10.1016\/j.nbd.2024.106550","article-title":"Brain development and bioenergetic changes","volume":"199","author":"Rajan","year":"2024","journal-title":"Neurobiol. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13229-020-00412-8","article-title":"Major motor and gait deficits with sexual dimorphism in a Shank3 mutant mouse model","volume":"12","author":"Matas","year":"2021","journal-title":"Mol. Autism."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"eaaz3267","DOI":"10.1126\/scitranslmed.aaz3267","article-title":"Autism-associated SHANK3 mutations impair maturation of neuromuscular junctions and striated muscles","volume":"12","author":"Lutz","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/s41392-023-01481-w","article-title":"The blood-brain barrier: Structure, regulation, and drug delivery","volume":"8","author":"Wu","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.addr.2019.11.009","article-title":"The blood-brain barrier: Physiology and strategies for drug delivery","volume":"165\u2013166","author":"Pandit","year":"2020","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e1706759","DOI":"10.1002\/adma.201706759","article-title":"Cell Membrane Coating Nanotechnology","volume":"30","author":"Fang","year":"2018","journal-title":"Adv. Mater."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.apsb.2016.02.001","article-title":"Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: Current perspectives and future challenges","volume":"6","author":"Ha","year":"2016","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1007\/s13346-022-01252-0","article-title":"Cell membrane-coated nanoparticles: A novel multifunctional biomimetic drug delivery system","volume":"13","author":"Liu","year":"2023","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2306","DOI":"10.1016\/j.apsb.2020.11.023","article-title":"Evolution of blood-brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies","volume":"11","author":"Han","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.jconrel.2023.06.023","article-title":"Cell membrane-based biomimetic vehicles for effective central nervous system target delivery: Insights and challenges","volume":"360","author":"Wu","year":"2023","journal-title":"J. Control Release"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/s41398-020-01086-9","article-title":"The influence of circadian rhythms and aerobic glycolysis in autism spectrum disorder","volume":"10","author":"Vallee","year":"2020","journal-title":"Transl. Psychiatry"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/8\/951\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T04:26:11Z","timestamp":1785644771000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/8\/951"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,31]]},"references-count":37,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["pharmaceutics18080951"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18080951","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,31]]}}}