Targeting the PGRN‐BMP Lysosomal Axis With NPs@PGRN Reverses Immunometabolic Dysfunction in Chronic Septic Arthritis
Source abstract
Abstract
ABSTRACT Chronic septic arthritis, often progressing to refractory infection due to intracellular bacterial persistence, is accompanied by dynamic macrophage immunometabolic reprogramming. Prolonged intracellular bacterial survival drives lipid metabolic remodeling in macrophages, leading to progressive accumulation of bis(monoacylglycero)phosphate (BMP), regulated by progranulin (PGRN). Mechanistically, PGRN maintains lysosomal homeostasis through direct interaction with BMP. PGRN deficiency disrupts lysosomal integrity, induces immunosuppressive polarization, and facilitates bacterial immune evasion. To address this, a dual‐targeting nanoparticle system (NPs@PGRN) targeting the “PGRN‐BMP‐lysosome” axis was developed. NPs@PGRN restores lysosomal bactericidal capacity via PGRN replenishment, significantly reduces bacterial burdens, and reprograms macrophage immunophenotypes toward antimicrobial competence. This study elucidates the central role of lipid‐immune crosstalk in chronic joint infection pathogenesis and provides a novel therapeutic strategy for it.
Source: crossref · Quality: baseline
Research context
OpenAlex topics: Amyotrophic Lateral Sclerosis Research · Autophagy in Disease and Therapy · Immune cells in cancer
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Department of Orthopedics, The Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang P. R. China
Orthopedics Research Institute of Zhejiang University Hangzhou Zhejiang P. R. China
Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, The Second Affiliated Hospital Zhejiang University Hangzhou Zhejiang P. R. China
Clinical Research Center of Motor System Disease of Zhejiang Province Hangzhou Zhejiang P. R. China
State Key Laboratory of Transvascular Implantation Devices Hangzhou P. R. China
Zhejiang Key Laboratory of Smart Biomaterials, Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering Zhejiang University Hangzhou P. R. China
Funding
National Natural Science Foundation of China
References (77)
Show source-provided references
1. 10.1016/j.biomaterials.2025.12324910.1016/j.biomaterials.2025.123249 ↗
2. 10.1126/sciadv.adp397610.1126/sciadv.adp3976 ↗
3. 10.1038/s41577-024-01080-y10.1038/s41577-024-01080-y ↗
4. 10.1126/sciadv.ado174910.1126/sciadv.ado1749 ↗
5. 10.1016/S1074-7613(00)80119-310.1016/S1074-7613(00)80119-3 ↗
6. 10.1038/ncomms1501510.1038/ncomms15015 ↗
7. 10.1073/pnas.25047649710.1073/pnas.250476497 ↗
8. 10.1093/femsre/fuac04110.1093/femsre/fuac041 ↗
9. 10.1016/j.immuni.2016.02.02610.1016/j.immuni.2016.02.026 ↗
10. 10.1021/acs.est.3c0662710.1021/acs.est.3c06627 ↗
11. 10.1002/jev2.1208010.1002/jev2.12080 ↗
12. 10.1080/15548627.2022.205404010.1080/15548627.2022.2054040 ↗
13. 10.1016/j.immuni.2021.08.00510.1016/j.immuni.2021.08.005 ↗
14. 10.1186/s13045-023-01478-610.1186/s13045-023-01478-6 ↗
15. 10.1126/science.aba802610.1126/science.aba8026 ↗
16. 10.1016/j.mib.2025.10261210.1016/j.mib.2025.102612 ↗
17. 10.1038/s41579-023-00852-y10.1038/s41579-023-00852-y ↗
18. 10.1002/adma.20251184010.1002/adma.202511840 ↗
19. 10.34133/research.084410.34133/research.0844 ↗
20. 10.1038/nri307310.1038/nri3073 ↗
21. 10.1016/j.immuni.2020.09.01410.1016/j.immuni.2020.09.014 ↗
22. 10.1002/adma.20230477410.1002/adma.202304774 ↗
23. 10.1073/pnas.190488511610.1073/pnas.1904885116 ↗
24. 10.1038/s41590-023-01430-310.1038/s41590-023-01430-3 ↗
25. 10.1038/s41467-022-34532-x10.1038/s41467-022-34532-x ↗
26. 10.1126/science.adg928810.1126/science.adg9288 ↗
27. 10.1016/j.semcdb.2014.04.01010.1016/j.semcdb.2014.04.010 ↗
28. 10.1016/j.cell.2024.09.03610.1016/j.cell.2024.09.036 ↗
29. 10.1016/j.cell.2021.08.00210.1016/j.cell.2021.08.002 ↗
30. 10.1126/scitranslmed.adj730810.1126/scitranslmed.adj7308 ↗
31. 10.1016/j.molmed.2020.07.00410.1016/j.molmed.2020.07.004 ↗
32. 10.1038/s41467-024-45692-310.1038/s41467-024-45692-3 ↗
33. PLA2G15 is a Lysosomal BMP Hydrolase and Its Targeting Ameliorates Lysosomal Disease
34. 10.1038/s41467-021-21186-410.1038/s41467-021-21186-4 ↗
35. 10.1038/nrmicro.2017.4210.1038/nrmicro.2017.42 ↗
36. 10.1016/j.pharmthera.2024.10875610.1016/j.pharmthera.2024.108756 ↗
37. 10.1016/j.ijmm.2013.11.01110.1016/j.ijmm.2013.11.011 ↗
38. 10.1053/j.gastro.2015.07.06410.1053/j.gastro.2015.07.064 ↗
39. 10.1016/j.bcp.2023.11546510.1016/j.bcp.2023.115465 ↗
40. 10.1016/j.pharmthera.2023.10845510.1016/j.pharmthera.2023.108455 ↗
41. 10.1038/ncomms1346410.1038/ncomms13464 ↗
42. 10.3390/ijms24211552810.3390/ijms242115528 ↗
43. 10.1038/nri.2015.410.1038/nri.2015.4 ↗
44. 10.1016/j.celrep.2023.11261710.1016/j.celrep.2023.112617 ↗
45. 10.1016/j.immuni.2013.05.01510.1016/j.immuni.2013.05.015 ↗
46. Modulation of Inflammation and Immunity by Omega‐3 Fatty Acids: a Possible Role for Prevention and to Halt Disease Progression in Autoimmune, Viral, and Age‐related Disorders
47. 10.3390/ijms2121806710.3390/ijms21218067 ↗
48. 10.1038/s43587-024-00595-210.1038/s43587-024-00595-2 ↗
49. 10.1038/s41380-025-03043-810.1038/s41380-025-03043-8 ↗
50. 10.1016/j.cmet.2025.04.01510.1016/j.cmet.2025.04.015 ↗
51. 10.1038/s41586-025-08942-y10.1038/s41586-025-08942-y ↗
52. 10.1146/annurev-biochem-092823-11381410.1146/annurev-biochem-092823-113814 ↗
53. 10.1016/j.tcb.2022.09.00610.1016/j.tcb.2022.09.006 ↗
54. 10.1186/s13024-025-00829-w10.1186/s13024-025-00829-w ↗
55. 10.1186/s40035-025-00475-810.1186/s40035-025-00475-8 ↗
56. 10.1186/s12974-025-03370-110.1186/s12974-025-03370-1 ↗
57. 10.1186/s12974-023-02965-w10.1186/s12974-023-02965-w ↗
58. 10.1126/sciadv.aaz476710.1126/sciadv.aaz4767 ↗
59. 10.1016/j.peptides.2003.12.00910.1016/j.peptides.2003.12.009 ↗
60. 10.1021/acsnano.5c0803810.1021/acsnano.5c08038 ↗
61. 10.1080/21505594.2025.255378910.1080/21505594.2025.2553789 ↗
62. 10.1002/advs.20240925110.1002/advs.202409251 ↗
63. CXCL16/CXCR6/TGF‐β Feedback Loop between M‐MDSCs and Treg Inhibits Anti‐Bacterial Immunity during Biofilm Infection
64. Hybrid Outer Membrane Vesicles with Genetically Engineering for Treatment of Implant‐Associated Infections and Relapse Prevention through Host Immunomodulation
65. 10.1002/adma.20241146810.1002/adma.202411468 ↗
66. 10.1021/acsnano.5c1029510.1021/acsnano.5c10295 ↗
67. 10.1016/j.biomaterials.2025.12337610.1016/j.biomaterials.2025.123376 ↗
68. 10.1126/sciadv.adr191110.1126/sciadv.adr1911 ↗
69. 10.1038/s41586-025-08942-y10.1038/s41586-025-08942-y ↗
70. 10.1016/j.phrs.2025.10795710.1016/j.phrs.2025.107957 ↗
71. 10.1186/s13024-025-00873-610.1186/s13024-025-00873-6 ↗
72. 10.1074/jbc.RA119.01116410.1074/jbc.RA119.011164 ↗
73. 10.1002/art.2749110.1002/art.27491 ↗
74. 10.1186/ar369410.1186/ar3694 ↗
75. 10.1111/nyas.1490510.1111/nyas.14905 ↗
76. 10.1186/s13045-025-01667-510.1186/s13045-025-01667-5 ↗
77. 10.1038/s41419-024-07233-010.1038/s41419-024-07233-0 ↗