{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T05:01:56Z","timestamp":1790226116577,"version":"4.1.0"},"reference-count":34,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["NSFC 21476054"],"award-info":[{"award-number":["NSFC 21476054"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["NSFC 21476054"],"award-info":[{"award-number":["NSFC 21476054"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Natural Science Foundation of Heilongjiang Province","award":["B201407"],"award-info":[{"award-number":["B201407"]}]},{"name":"China Scholarship Council","award":["201608930006"],"award-info":[{"award-number":["201608930006"]}],"id":[{"id":"https:\/\/ror.org\/04atp4p48","id-type":"ROR","asserted-by":"crossref"}]},{"award":["201608930006"],"award-info":[{"award-number":["201608930006"]}],"id":[{"id":"https:\/\/ror.org\/04atp4p48","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The clinical management of ischemic stroke is severely constrained by the blood\u2013brain barrier (BBB), which restricts therapeutic drug access to the brain parenchyma, and the rapid systemic clearance of neuroprotective agents such as breviscapine (Bre). To overcome this dual challenge, we engineered a dual-targeting nanocarrier, L57&amp;PGP-PEG-PAMAM, designed to sequentially traverse the BBB and anchor within the ischemic inflammatory microenvironment. This construct employs a PEGylated fifth-generation polyamidoamine (PAMAM) dendrimer scaffold functionalized with two distinct peptides: L57, which mediates transcytosis via LRP1 receptors on the BBB, and PGP, which targets CXCR2 receptors overexpressed on infiltrating neutrophils at the lesion. The resulting nano particles exhibited a hydrodynamic diameter of 140.2 \u00b1 0.6 nm (zeta potential: 9.32 mV) and encapsulated Bre with a loading capacity of 20.12% and encapsulation efficiency of 71.78%, displaying sustained release (54.6% over 72 h). Crucially, in vivo fluorescence imaging confirmed markedly superior brain accumulation relative to non-targeted and PEGylated-only controls, while in a rat MCAO model, the formulation reduced infarct volume to 21.7 \u00b1 6.4%, improved neurological scores to 1.52 \u00b1 0.28, and suppressed pro-inflammatory IL-15\/IL-27 levels\u2014collectively outperforming free Bre. This work establishes a robust \u201ccross-and-capture\u201d strategy that effectively decouples BBB penetration from lesion-specific retention for ischemic stroke therapy.<\/jats:p>","DOI":"10.3390\/molecules31193363","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T08:17:54Z","timestamp":1790065074000},"page":"3363","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cross-and-Capture: A Dual-Ligand PAMAM Nanocarrier for Sequential BBB Penetration and Ischemic Lesion Retention of Breviscapine"],"prefix":"10.3390","volume":"31","author":[{"given":"Haoran","family":"Guo","sequence":"first","affiliation":[{"name":"School of Materials Science and Chemical Engineering, Harbin University of Science and Technology, Harbin 150040, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Dandan","family":"Han","sequence":"additional","affiliation":[{"name":"School of Materials Science and Chemical Engineering, Harbin University of Science and Technology, Harbin 150040, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5934-2118","authenticated-orcid":false,"given":"Xin","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Materials Science and Chemical Engineering, Harbin University of Science and Technology, Harbin 150040, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3327","DOI":"10.1007\/s40843-022-2484-1","article-title":"A blood-brain barrier crossing peptide","volume":"66","author":"Li","year":"2023","journal-title":"Sci. China Mater."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6985","DOI":"10.1039\/D5RA07719B","article-title":"Synergistic NIR-polydopamine nanotherapy for blood\u2013brain barrier crossing and Parkinson\u2019s disease intervention","volume":"16","author":"Xia","year":"2026","journal-title":"RSC Adv."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2524","DOI":"10.1007\/s10118-026-3660-3","article-title":"Boosting Blood-Brain Barrier Crossing with a Mannosylated Nanocarrier","volume":"44","author":"Gu","year":"2026","journal-title":"Chin. J. Polym. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"15550","DOI":"10.1021\/acs.nanolett.5c03705","article-title":"Chemically Designed Functional Nanomicelles for Blood\u2013Brain Barrier Crossing","volume":"25","author":"Sarkar","year":"2025","journal-title":"Nano Lett."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"29437","DOI":"10.1021\/acsami.5c05429","article-title":"Tailored Mesoporous Silica Nanoparticles and the Chick Chorioallantoic Membrane: A Promising Strategy and Model for Efficient Blood-Brain Barrier Crossing","volume":"17","author":"Lin","year":"2025","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1186\/s13020-025-01239-2","article-title":"Biomimetic nanodelivery system with simultaneous blood\u2013brain barrier-crossing and neuroprotective abilities for anti-parkinsonian therapy","volume":"20","author":"Yin","year":"2025","journal-title":"Chin. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"588499","DOI":"10.2147\/IJN.S588499","article-title":"Nanomaterial-Based Drug Delivery Systems for Ischemic Stroke: From Blood-Brain Barrier Crossing to Neuroprotection","volume":"21","author":"He","year":"2026","journal-title":"Int. J. Nanomed."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1021\/acs.bioconjchem.4c00073","article-title":"Transthyretin-Penetratin: A Potent Fusion Protein Inhibitor against Alzheimer\u2019s Amyloid-\u03b2 Fibrillogenesis with High Blood Brain Barrier Crossing Capability","volume":"35","author":"Wang","year":"2024","journal-title":"Bioconjug. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s13205-025-04378-3","article-title":"Breaking barriers: Exploring blood\u2013brain barrier crossing mechanisms with nanomedicine for effective glioma treatment","volume":"15","author":"Ali","year":"2025","journal-title":"3 Biotech"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1039\/D4BM00043A","article-title":"Blood\u2013brain barrier-crossing dendrimers for glioma theranostics","volume":"12","author":"Wang","year":"2024","journal-title":"Biomater. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.jconrel.2024.06.005","article-title":"PEG length effect of peptide-functional liposome for blood brain barrier (BBB) penetration and brain targeting","volume":"372","author":"Du","year":"2024","journal-title":"J. Control. Release"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s12645-023-00211-9","article-title":"Advances in blood\u2013brain barrier-crossing nanomedicine for anti-glioma","volume":"14","author":"Liu","year":"2023","journal-title":"Cancer Nanotechnol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"145514","DOI":"10.1016\/j.cej.2023.145514","article-title":"A dual receptor targeting and blood\u2013brain barrier penetrating co-drug-loaded particle mediating inhibition of oxidative phosphorylation for targeted therapy of glioblastoma","volume":"473","author":"Sun","year":"2023","journal-title":"Chem. Eng. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5150","DOI":"10.7150\/thno.123534","article-title":"Dual-ligand curcin-loaded hybrid solid lipid nanoparticles achieve durable gliosarcoma remission while preserving neuro-behavioral function","volume":"16","author":"Sakamoto","year":"2026","journal-title":"Theranostics"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"123730","DOI":"10.1016\/j.biomaterials.2025.123730","article-title":"Dual-responsive nanoparticle system for enhanced blood-brain barrier crossing and glioblastoma penetration","volume":"327","author":"Zheng","year":"2025","journal-title":"Biomaterials"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4698","DOI":"10.1039\/D5NR05008A","article-title":"Ligand content-dependent exocytosis governs the blood\u2013brain barrier transcytosis of nanocarriers","volume":"18","author":"Zhang","year":"2026","journal-title":"Nanoscale"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1038\/s41587-024-02487-7","article-title":"Intravenous administration of blood\u2013brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system","volume":"43","author":"Wang","year":"2024","journal-title":"Nat. Biotechnol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/011570159X450934260313135820","article-title":"Recent Advances in Blood-brain Barrier (BBB)-Penetrating Nanomaterialsfor Neurological Disease Imaging, Diagnosis, and Therapy","volume":"24","author":"Liu","year":"2026","journal-title":"Curr. Neuropharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e2516465122","DOI":"10.1073\/pnas.2516465122","article-title":"A SynB1-conjugated antibody cocktail crosses the blood\u2013brain barrier to produce a therapeutic effect on rabies","volume":"122","author":"Ren","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"14222","DOI":"10.1039\/D6SC00011H","article-title":"Chimeric peptide-based radiopharmaceuticals for glioblastoma imaging and therapy by targeting mHsp70 and enhancing BBB penetration","volume":"17","author":"Schuderer","year":"2026","journal-title":"Chem. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"123306","DOI":"10.1016\/j.ijpharm.2023.123306","article-title":"A dual-targeting peptide for glioblastoma screened by phage display peptide library biopanning combined with affinity-adaptability analysis","volume":"644","author":"Li","year":"2023","journal-title":"Int. J. Pharm."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Yang, L., Yin, Y., Liu, X., and Guo, B. (2026). Aptamer-Based Delivery of Genes and Drugs Across the Blood\u2013Brain Barrier. Pharmaceuticals, 19.","DOI":"10.3390\/ph19010164"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"100738","DOI":"10.1016\/j.mtadv.2026.100738","article-title":"A BBB-penetrated, microglia-targeted, and hypoxia-responsive nanogel for treating ischemic stroke","volume":"29","author":"Xia","year":"2026","journal-title":"Mater. Today Adv."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"eadg6618","DOI":"10.1126\/sciadv.adg6618","article-title":"Primate-conserved carbonic anhydrase IV and murine-restricted LY6C1 enable blood-brain barrier crossing by engineered viral vectors","volume":"9","author":"Shay","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1080\/17425247.2023.2255138","article-title":"Receptor\u2013mediated transcytosis of macromolecules across the blood\u2013brain barrier","volume":"20","author":"Baghirov","year":"2023","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e2208097","DOI":"10.1002\/adma.202208097","article-title":"Maximum emission peak over 1500 nm of organic assembly for blood\u2013brain barrier-crossing NIR-IIb phototheranostics of orthotopic glioblastoma","volume":"35","author":"Zhao","year":"2023","journal-title":"Adv. Mater."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"47835","DOI":"10.1021\/acsami.5c09651","article-title":"Molecular Windows into the Brain: Advances in BBB-Penetrable NIR Fluorescent Imaging Probes","volume":"17","author":"Niu","year":"2025","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2400100","DOI":"10.1002\/adtp.202400100","article-title":"Surface modified glucose-derived, blood\u2013brain barrier-crossing nanospheres dually targets macrophage and cancer cells for effective in situ anti-glioma effect","volume":"7","author":"Jaggarapu","year":"2024","journal-title":"Adv. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6623031","DOI":"10.1155\/2021\/6623031","article-title":"A Nanogel with Effective Blood-Brain Barrier Penetration Ability through Passive and Active Dual-Targeting Function","volume":"2021","author":"Liu","year":"2021","journal-title":"J. Nanomater."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"453","DOI":"10.34172\/apb.2024.033","article-title":"Discovery of a novel dual targeting peptide for human glioma: From in silico simulation to acting as targeting ligand","volume":"14","author":"Saeedi","year":"2024","journal-title":"Adv. Pharm. Bull."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1038\/s41563-024-02114-5","article-title":"Blood\u2013brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system","volume":"24","author":"Wang","year":"2025","journal-title":"Nat. Mater."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"12161","DOI":"10.1021\/acsami.3c14709","article-title":"Angiopep-2-functionalized lipid cubosomes for blood\u2013brain barrier crossing and glioblastoma treatment","volume":"16","author":"Cai","year":"2024","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2466","DOI":"10.1021\/ma00163a029","article-title":"Dendritic macromolecules: Synthesis of starburst dendrimers","volume":"19","author":"Tomalia","year":"1986","journal-title":"Macromolecules"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1016\/j.addr.2005.07.005","article-title":"The use of mucoadhesive polymers in ocular drug delivery","volume":"57","author":"Ludwig","year":"2005","journal-title":"Adv. Drug Deliv. Rev."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/19\/3363\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T04:27:15Z","timestamp":1790224035000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/19\/3363"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,22]]},"references-count":34,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["molecules31193363"],"URL":"https:\/\/doi.org\/10.3390\/molecules31193363","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,22]]}}}