Citation: Yaran Chang, Tian Chen, Mengying Wang, Hanyu Yuan, Caixia Wang, Zhihong Liu, Qiaosheng Pu, Guangsheng Guo, Xiayan Wang. Mass spectrometry-based multi-omics analysis reveals the mechanism of angiopep-2-functionalized nanoparticles crossing the blood-brain barrier[J]. Chinese Chemical Letters, ;2026, 37(12): 112770. doi: 10.1016/j.cclet.2026.112770 shu

Mass spectrometry-based multi-omics analysis reveals the mechanism of angiopep-2-functionalized nanoparticles crossing the blood-brain barrier

Yaran Chang ^{a, b} ,
Tian Chen ^b ,
Mengying Wang ^b ,
Hanyu Yuan ^b ,
Caixia Wang ^c ,
Zhihong Liu ^{c, *,} ,
Qiaosheng Pu ^d ,
Guangsheng Guo ^b ,
Xiayan Wang ^{b, *,}

a.
Beijing Key Laboratory of Theory and Technology for Advanced Batteries Materials, School of Materials Science and Engineering, Peking University, Beijing 100871, China
b.
State Key Laboratory of Materials Low-Carbon Recycling, Center of Excellence for Environmental Safety and Biological Effects, Department of Chemistry, College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China
c.
College of Health Science and Engineering, Hubei University, Wuhan 430062, China
d.
State Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous Metals Chemistry and Resources Utilization of Gansu Province, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China

zhhliu@whu.edu.cn

xiayanwang@bjut.edu.cn

Received Date: 30 December 2025
Revised Date: 25 February 2026
Accepted Date: 13 April 2026
Available Online: 16 April 2026

Figures(5)

The blood-brain barrier (BBB) is a dynamic and selective barrier that maintains cerebral homeostasis but severely restricts drug delivery to the central nervous system, hampering the diagnosis and treatment of neurological disorders. Understanding how nanocarriers cross the BBB is thus essential for designing safe and efficient brain-targeted delivery systems. Here, we established an in vitro BBB model with enhanced barrier integrity using a three-cell-type co-culture in a Transwell system. Angiopep-2-functionalized nanoparticles (ANG NPs) were developed to investigate nanoparticle transport mechanisms. Integrated multi-omics analysis revealed that unmodified nanoparticles lack a defined transport pathway, whereas ANG-functionalized nanoparticles cross the BBB through receptor-mediated transcytosis involving lysosomal and phagosomal pathways. Both nanoparticles activated the ABC transporter pathway, leading to the efflux of nonspecific substrates back into the bloodstream. This multi-omics approach systematically elucidated distinct transport mechanisms, holding promise for informing the rational design of safer and more efficient brain-targeted nanocarriers.
- Blood-brain barrier,
- Proteomics,
- Metabolomics,
- Crossing mechanism,
- Ang-functionalized nanoparticles
1. [1]
  S.M. Shi, R.J. Suh, D.J. Shon, et al., Nature 639 (2025) 985–994. doi: 10.1038/s41586-025-08589-9
2. [2]
  C.D. Arvanitis, G.B. Ferraro, R.K. Jain, Nat. Rev. Cancer 20 (2020) 26–41. doi: 10.1038/s41568-019-0205-x
3. [3]
  P. Wang, Y. Wang, P. Li, et al., Chin. Chem. Lett. 34 (2023) 107691. doi: 10.1016/j.cclet.2022.07.034
4. [4]
  C. Xie, J. Liao, N. Zhang, et al., Chin. Chem. Lett. 35 (2024) 109149. doi: 10.1016/j.cclet.2023.109149
5. [5]
  R. Rust, H. Yin, B. Achón Buil, A.P. Sagare, K. Kisler, Brain 148 (2025) 2262–2282. doi: 10.1093/brain/awaf068
6. [6]
  G. Li, Z. Li, Y. Sun, et al., Chin. Chem. Lett. 37 (2026) 111524. doi: 10.1016/j.cclet.2025.111524
7. [7]
  Z. Li, C. Wang, M. Zhang, et al., Nano Today 39 (2021) 101239. doi: 10.1016/j.nantod.2021.101239
8. [8]
  Q. Tan, S. Zhao, T. Xu, et al., Coord. Chem. Rev. 494 (2023) 215344. doi: 10.1016/j.ccr.2023.215344
9. [9]
  M. Beygi, F. Oroojalian, S. Azizi-Arani, et al., Adv. Funct. Mater. 34 (2024) 2310881. doi: 10.1002/adfm.202310881
10. [10]
  D. Lu, Y. Sun, Y. Luan, W. He, Pharmaceut. Sci. Adv. 2 (2024) 100041. doi: 10.1016/j.pscia.2024.100041
11. [11]
  E.S. Seven, Y.B. Seven, Y. Zhou, et al., Nanoscale Adv. 3 (2021) 3942–3953. doi: 10.1039/d1na00145k
12. [12]
  T. Guo, J.A. Steen, M. Mann, Nature 638 (2025) 901–911. doi: 10.1038/s41586-025-08584-0
13. [13]
  C.S. Movassaghi, J. Sun, Y. Jiang, et al., Anal. Chem. 97 (2025) 4728–4749. doi: 10.1021/acs.analchem.4c06750
14. [14]
  C. Lin, Q. Tian, S. Guo, et al., Molecules 29 (2024) 2198. doi: 10.3390/molecules29102198
15. [15]
  S. Qiu, Y. Cai, H. Yao, et al., Signal Transduct. Target. Ther. 8 (2023) 132. doi: 10.1038/s41392-023-01399-3
16. [16]
  Y. Wu, Z. Chen, F. Chen, et al., Anal. Chem. 97 (2025) 7968–7977. doi: 10.1021/acs.analchem.5c00365
17. [17]
  A.V. Petrovskaya, E.P. Barykin, A.M. Tverskoi, et al., Mol. Biol. 56 (2022) 1020–1027. doi: 10.1134/s0026893322060140
18. [18]
  W. Tang, W. Fan, J. Lau, et al., Chem. Soc. Rev. 48 (2019) 2967–3014. doi: 10.1039/c8cs00805a
19. [19]
  S. Palma-Florez, A. Lopez-Canosa, F. Moralez-Zavala, et al., J. Nanobiotechnol. 21 (2023) 115. doi: 10.1186/s12951-023-01798-2
20. [20]
  Z.H. Mok, Pharmaceut. Sci. Adv. 2 (2024) 100031. doi: 10.1016/j.pscia.2023.100031
21. [21]
  G. Jia, Y. Jiang, X. Li, Pharmaceut. Sci. Adv. 2 (2024) 100048. doi: 10.1016/j.pscia.2024.100048
22. [22]
  A.C. di Polidoro, A. Cafarchio, D. Vecchione, et al., Molecules 27 (2022) 6696. doi: 10.3390/molecules27196696
23. [23]
  G. Kong, J. Liu, J. Wang, et al., ACS Nano 19 (2025) 4582–4600. doi: 10.1021/acsnano.4c14675
24. [24]
  S. Habib, M. Singh, Polymers 14 (2022) 712. doi: 10.3390/polym14040712
25. [25]
  L.J. Zhang, L. Xia, H.Y. Xie, Z.L. Zhang, D.W. Pang, Anal. Chem. 91 (2019) 532–547. doi: 10.1021/acs.analchem.8b04721
26. [26]
  A.M. Wagner, J.M. Knipe, G. Orive, N.A. Peppas, Acta Biomater. 94 (2019) 44–63. doi: 10.1016/j.actbio.2019.05.022
27. [27]
  A. Ishihara, M. Yamauchi, T. Tsuchiya, et al., J. Biomater. Sci. Polym. Ed. 23 (2012) 2055–2068. doi: 10.1163/092050611x605933
28. [28]
  L. Sercombe, T. Veerati, F. Moheimani, et al., Front. Pharmacol. 6 (2015) 286.
29. [29]
  Y. Jiang, W. Yang, J. Zhang, F. Meng, Z. Zhong, Adv. Mater. 30 (2018) 1800316. doi: 10.1002/adma.201800316
30. [30]
  G. Sonavane, K. Tomoda, K. Makino, Colloid Surf. B: Biointerfaces 66 (2008) 274–280. doi: 10.1016/j.colsurfb.2008.07.004
31. [31]
  S.A. Kulkarni, S.S. Feng, Pharm. Res. 30 (2013) 2512–2522. doi: 10.1007/s11095-012-0958-3
32. [32]
  L. Ribovski, N.M. Hamelmann, J.M.J. Paulusse, Pharmaceutics 13 (2021) 2045. doi: 10.3390/pharmaceutics13122045
33. [33]
  C. Saraiva, C. Praca, R. Ferreira, et al., J. Control. Release 235 (2016) 34–47. doi: 10.1016/j.jconrel.2016.05.044
34. [34]
  X. Liu, R. Wu, Y. Li, et al., Biomater. Sci. 9 (2021) 2903–2916. doi: 10.1039/d1bm00020a
35. [35]
  Q. Song, B. Meng, H. Xu, Z. Mao, Transl. Neurodegener. 9 (2020) 17. doi: 10.1186/s40035-020-00196-0
36. [36]
  R.S. Flannagan, V. Jaumouillé, S. Grinstein, Annu. Rev. Pathol. Mech. Dis. 7 (2012) 61–98. doi: 10.1146/annurev-pathol-011811-132445
37. [37]
  R. Imle, B.T. Wang, N. Stützenberger, et al., Sci. Rep. 9 (2019) 14248. doi: 10.1038/s41598-019-50566-6
38. [38]
  S. Shen, W. Zhang, Rev. Neurosci. 21 (2010) 29–53.
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2. [2]
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6. [6]
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7. [7]
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8. [8]
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9. [9]
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11. [11]
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