{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:47:26Z","timestamp":1787510846291,"version":"build-2736575974"},"reference-count":36,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,15]],"date-time":"2026-02-15T00:00:00Z","timestamp":1771113600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"State Key Laboratory for Integration and Innovation of Classic Formula and Modern Chinese Medicine","award":["LSLSKL 20240105"],"award-info":[{"award-number":["LSLSKL 20240105"]}]},{"DOI":"10.13039\/501100005046","name":"Heilongjiang Province Natural Science Foundation","doi-asserted-by":"crossref","award":["LH2023H050"],"award-info":[{"award-number":["LH2023H050"]}],"id":[{"id":"10.13039\/501100005046","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Lateral Project of Dong\u2019e Ejiao Co., Ltd.","award":["22042240002"],"award-info":[{"award-number":["22042240002"]}]},{"name":"Lateral Project of Nanjing Jiumingyuan Biotechnology Co., Ltd.","award":["22012250004"],"award-info":[{"award-number":["22012250004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Luteolin (Ltn), a natural flavonoid, effectively inhibits microglial activation in Alzheimer\u2019s disease (AD) with promising therapeutic potential, but its efficacy is severely limited by the blood\u2013brain barrier (BBB). To overcome this obstacle, this study prepared poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs)\u2014designated as TGN\/RAP12-RBC-NPs@Ltn\u2014which were coated with red blood cell membranes (RBCm) functionalized with two peptides, TGN (TGNYKALHPHN) and RAP12 (EAKIEKHNHYQK). The results demonstrated that TGN significantly enhanced BBB permeability, while RAP12 enabled effective targeting and delivery of TGN\/RAP12-RBC-NPs@Ltn to microglial mitochondria in the brain. In addition, the presence of RBCm significantly inhibited the phagocytosis of NPs by macrophages, exerting a notable role in immune evasion. Meanwhile, the study confirmed that encapsulating Ltn within NPs significantly enhanced cognitive function in APP\/PS1 mice, modulated the expression of key mitochondrial metabolic enzymes\u2014pyruvate dehydrogenase (PDH) and its phosphorylated forms (pS232PDH, pS293PDH, pS300PDH)\u2014in microglia, thereby ameliorating mitochondrial dysfunction and effectively regulating the neuroinflammatory environment in the mouse brain, and ultimately contributed to therapeutic efficacy. From this, it could be seen that TGN\/RAP12-RBC-NPs@Ltn could significantly enhance the therapeutic effect of Ltn on AD, providing an effective treatment strategy for delaying the progression of AD.<\/jats:p>","DOI":"10.3390\/molecules31040671","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T14:55:47Z","timestamp":1771253747000},"page":"671","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Luteolin-Loaded TGN\/RAP12 Dual-Peptide Functionalized Nanoparticles: Synergistic Enhancement of BBB Penetration and Microglia Targeting in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"31","author":[{"given":"Shumeng","family":"Liu","sequence":"first","affiliation":[{"name":"Metabolomics Laboratory, Department of Pharmaceutical Analysis, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Xing","sequence":"additional","affiliation":[{"name":"Metabolomics Laboratory, Department of Pharmaceutical Analysis, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Na","sequence":"additional","affiliation":[{"name":"Key Laboratory of Photochemistry Biomaterials and Energy Storage Materials of Heilongjiang Province, School of Chemistry and Chemical Engineering, Harbin Normal University, Harbin 150000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Photochemistry Biomaterials and Energy Storage Materials of Heilongjiang Province, School of Chemistry and Chemical Engineering, Harbin Normal University, Harbin 150000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Photochemistry Biomaterials and Energy Storage Materials of Heilongjiang Province, School of Chemistry and Chemical Engineering, Harbin Normal University, Harbin 150000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhigang","family":"Wang","sequence":"additional","affiliation":[{"name":"Metabolomics Laboratory, Department of Pharmaceutical Analysis, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China"},{"name":"State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co., Ltd., Linyi 276005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0399-5085","authenticated-orcid":false,"given":"Ning","family":"Zhang","sequence":"additional","affiliation":[{"name":"Metabolomics Laboratory, Department of Pharmaceutical Analysis, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China"},{"name":"State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co., Ltd., Linyi 276005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuhong","family":"Wu","sequence":"additional","affiliation":[{"name":"Metabolomics Laboratory, Department of Pharmaceutical Analysis, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Geng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Photochemistry Biomaterials and Energy Storage Materials of Heilongjiang Province, School of Chemistry and Chemical Engineering, Harbin Normal University, Harbin 150000, China"},{"name":"State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co., Ltd., Linyi 276005, 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