Citation: Huxiao Sun, Jin Li, Mengsi Zhan, Yu Zou, Caiyun Zhang, Serge Mignani, Regis Laurent, Jean-Pierre Majoral, Xiangyang Shi, Mingwu Shen. Asymmetric bioactive phosphorus dendrimers deliver bromelain for enhanced anti-inflammation and chondroprotection therapy of osteoarthritis[J]. Chinese Chemical Letters, ;2026, 37(3): 111446. doi: 10.1016/j.cclet.2025.111446 shu

Asymmetric bioactive phosphorus dendrimers deliver bromelain for enhanced anti-inflammation and chondroprotection therapy of osteoarthritis

Huxiao Sun ^{a, 1} ,
Jin Li ^{a, 1} ,
Mengsi Zhan ^a ,
Yu Zou ^{a, *,} ,
Caiyun Zhang ^a ,
Serge Mignani ^{b, c} ,
Regis Laurent ^{d, e} ,
Jean-Pierre Majoral ^{d, e} ,
Xiangyang Shi ^{a, b, *,} ,
Mingwu Shen ^{a, *,}

a.
State Key Laboratory of Advanced Fiber Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China
b.
CQM-Centro de Química da Madeira, Universidade da Madeira, Campus Universitário da Penteada, Funchal 9020-105, Portugal
c.
Centre d’Etudes et de Recherche sur le Medicament de Normandie (CERMN), Université de Caen Normandie, Caen 14032, France
d.
Laboratoire de Chimie de Coordination du CNRS, 205 Route de Narbonne, CEDEX 4, Toulouse 31077, France
e.
Université Toulouse, 118 Route de Narbonne, CEDEX 4, Toulouse 31077, France

yuzou@dhu.edu.cn

xshi@dhu.edu.cn

mwshen@dhu.edu.cn

Received Date: 23 March 2025
Revised Date: 8 June 2025
Accepted Date: 10 June 2025
Available Online: 11 June 2025

Figures(6)

It is still challenging to develop nanomedicines with full-active and simple components to tackle osteoarthritis (OA) through restoration of inflammation and cartilage homeostasis. Here, we report the synthesis of a bioactive asymmetric phosphorus dendrimer bearing an azabisphosphonate (ABP) group, termed as G0.PD-ABP, by a divergent method for intracellular bromelain (Bro) delivery. The formed G0.PD-ABP/Bro nanocomplexes (NCs) exhibit a uniformly dispersed spherical shape with a mean size of 148.4 nm and can achieve more significant intracellular Bro delivery than symmetric phosphorus dendrimer (G0.PD) without ABP via the clathrin-mediated endocytosis pathway. Importantly, the NCs efficiently block the activation of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and nuclear factor kappa-B (NF-κB) by amplifying the anti-inflammatory function of Bro and synergizing with the immunomodulatory activity of dendrimers, thereby facilitating the polarization of macrophages towards M2 phenotype and down-regulating inflammatory cytokine secretion to lead to suppressed chondrocyte apoptosis. Compared with G0.PD/Bro NCs, an OA mouse model treated with G0.PD-ABP/Bro NCs demonstrates more remarkable alleviation of pathological features such as cartilage degradation, bone erosion, and synovial inflammation. This study emphasizes the positive contribution of structural asymmetry of phosphorus dendrimers in protein delivery and provides a viable strategy for the treatment of OA or other inflammatory diseases through enhanced immune modulation of macrophages.
- Phosphorus dendrimer,
- Bromelain,
- Macrophage M2 polarization,
- Anti-inflammation,
- Osteoarthritis
1. [1]
  H. Lu, J. Wei, K. Liu, et al., ACS Nano 17 (2023) 6131–6146. doi: 10.1021/acsnano.3c01789
2. [2]
  Z. Li, H. Lu, L. Fan, et al., Adv. Sci. 11 (2024) 2406942. doi: 10.1002/advs.202406942
3. [3]
  G. Li, S. Liu, Y. Chen, et al., Nat. Commun. 14 (2023) 3159. doi: 10.1038/s41467-023-38597-0
4. [4]
  X. Gao, L. Yan, W. Zhang, et al., Nano Today 53 (2023) 102047. doi: 10.1016/j.nantod.2023.102047
5. [5]
  C. Xie, Q. Sun, Y. Dong, et al., ACS Nano 17 (2023) 12842–12861. doi: 10.1021/acsnano.3c04241
6. [6]
  R. Deng, R. Zhao, Z. Zhang, et al., Sci. Transl. Med. 16 (2024) eadh9751. doi: 10.1126/scitranslmed.adh9751
7. [7]
  P. Chen, X. Liu, C. Gu, et al., Nature 612 (2022) 546–554. doi: 10.1038/s41586-022-05499-y
8. [8]
  X. Song, L. Gu, Q. Yang, et al., Chin. Chem. Lett. 34 (2023) 108079. doi: 10.1016/j.cclet.2022.108079
9. [9]
  S.H. Cui, Y. Yan, A. Lu, et al., ACS Nano 18 (2024) 8125–8142. doi: 10.1021/acsnano.3c11848
10. [10]
  X. He, S. He, G. Xiang, et al., Adv. Mater. 36 (2024) 2405943. doi: 10.1002/adma.202405943
11. [11]
  K. Zhou, C. Yang, K. Shi, et al., Biomaterials 295 (2023) 122036. doi: 10.1016/j.biomaterials.2023.122036
12. [12]
  Z. Zhou, F. Gong, P. Zhang, et al., Nano Res. 15 (2022) 3338–3345. doi: 10.1007/s12274-021-3864-3
13. [13]
  P. Wojdasiewicz, Ł. A. Poniatowski, D. Szukiewicz, Mediat Inflamm. (2014) 561459 2014.
14. [14]
  M. Zhan, H. Sun, Z. Wang, et al., ACS Nano 18 (2024) 10625–10641. doi: 10.1021/acsnano.4c00909
15. [15]
  H. Sun, M. Zhan, Y. Zou, et al., Biomaterials 316 (2025) 122999. doi: 10.1016/j.biomaterials.2024.122999
16. [16]
  V. Kumar, B. Mangla, S. Javed, et al., Food Funct. 14 (2023) 8101–8128. doi: 10.1039/d3fo01060k
17. [17]
  O. Insuan, P. Janchai, B. Thongchuai, et al., Curr. Issues Mol. Biol. 43 (2021) 93–106. doi: 10.3390/cimb43010008
18. [18]
  J.R. Huang, C.C. Wu, R.C.W. Hou, et al., Immunol. Invest. 37 (2008) 263–277. doi: 10.1080/08820130802083622
19. [19]
  L. Chen, H. Wang, Y. Cheng, Chin. Chem. Lett. 37 (2026) 111172. doi: 10.1016/j.cclet.2025.111172
20. [20]
  S. Guo, H. Xu, Z. Cheng, et al., Chin. Chem. Lett. 36 (2025) 111022. doi: 10.1016/j.cclet.2025.111022
21. [21]
  F. Hu, J. Qi, Y. Lu, et al., Chin. Chem. Lett. 34 (2023) 108250. doi: 10.1016/j.cclet.2023.108250
22. [22]
  J. Xu, Z. Li, Q. Fan, et al., Adv. Mater. 33 (2021) 2104355. doi: 10.1002/adma.202104355
23. [23]
  K. Liang, S. Ng, F. Lee, et al., Acta Biomater. 33 (2016) 142–152. doi: 10.1016/j.actbio.2016.01.011
24. [24]
  L. Shi, W. Wu, Y. Duan, et al., Angew. Chem. Int. Ed. 59 (2020) 19168–19174. doi: 10.1002/anie.202006890
25. [25]
  J.E. Chung, S. Tan, S.J. Gao, et al., Nat. Nanotechnol. 9 (2014) 907–912. doi: 10.1038/nnano.2014.208
26. [26]
  H. Sun, M. Zhan, A. Karpus, et al., ACS Nano 18 (2024) 2195–2209. doi: 10.1021/acsnano.3c09589
27. [27]
  Y. Peng, M. Zhan, A. Karpus, et al., ACS Nano 18 (2024) 10142–10155. doi: 10.1021/acsnano.3c13088
28. [28]
  J. Ma, M. Zhan, H. Sun, et al., Adv. Healthc. Mater. 13 (2024) 2401462. doi: 10.1002/adhm.202401462
29. [29]
  Y. Zou, S. Shen, A. Karpus, et al., Biomacromolecules 25 (2024) 1171–1179. doi: 10.1021/acs.biomac.3c01169
30. [30]
  M. Hayder, M. Poupot, M. Baron, et al., Sci. Transl. Med. 3 (2011) 81ra35.
31. [31]
  A.K. Sarkar, K. Debnath, H. Arora, et al., ACS Appl. Mater. Interfaces 14 (2022) 3199–3206. doi: 10.1021/acsami.1c22009
32. [32]
  H. Chang, J. Lv, X. Gao, et al., Nano Lett. 17 (2017) 1678–1684. doi: 10.1021/acs.nanolett.6b04955
33. [33]
  D. Prozeller, S. Morsbach, K. Landfester, Nanoscale 11 (2019) 19265–19273. doi: 10.1039/c9nr05790k
34. [34]
  M. Braia, D. Loureiro, G. Tubio, et al., Colloids Surf. B 155 (2017) 507–511. doi: 10.1016/j.colsurfb.2017.04.033
35. [35]
  C. Huo, G. Liu, M. Xu, et al., Spectrochim. Acta Part A 263 (2021) 120213. doi: 10.1016/j.saa.2021.120213
36. [36]
  X. Yang, M. Tan, J. Guo, et al., Adv. Funct. Mater. 34 (2024) 2401963. doi: 10.1002/adfm.202401963
37. [37]
  F. Zhou, J. Mei, S. Yang, et al., ACS Appl. Mater. Interfaces 12 (2020) 2009–2022. doi: 10.1021/acsami.9b16327
38. [38]
  S.K. Bedingfield, J.M. Colazo, F. Yu, et al., Nat. Biomed. Eng. 5 (2021) 1069–1083. doi: 10.1038/s41551-021-00780-3
39. [39]
  J. Li, L. Chen, C. Li, et al., Theranostics 12 (2022) 3407–3419. doi: 10.7150/thno.70701
40. [40]
  J. Yin, H. Zeng, K. Fan, et al., Cell Death Dis. 13 (2022) 567. doi: 10.1038/s41419-022-04962-y
41. [41]
  H. Wang, S. e. Su, X. An, et al., Bioact. Mater. 45 (2025) 496–508.
42. [42]
  M. Chen, J. Luo, H. Ji, et al., J. Funct. Foods 110 (2023) 105863. doi: 10.1016/j.jff.2023.105863
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