EXOSOME-BASED THERAPEUTICS TARGETING NLRP3 INFLAMMASOME IN DIABETIC KIDNEY DISEASE: A SYSTEMATIC REVIEW

Muhammad Ardhan  Hakim; Muhammad Rifqi Al  Azim; Aulia Cindy  Pratiwi; Kanaya Syafa  Amanda; Athaillah Faiz  Assyawal; Sultan Kemal  Dewantara; Arvando Yoga  Pratama; Nabil Abdillah Al Afif  Suma

doi:10.62710/fqs4jw22

Authors

Muhammad Ardhan Hakim Program Studi Sarjana Kedokteran, Fakultas Kedokteran, Universitas Andalas, Padang, Indonesia Author
Muhammad Rifqi Al Azim rogram Studi Profesi Dokter, Fakultas Kedokteran, Universitas Andalas, Padang, Indonesia Author
Aulia Cindy Pratiwi Program Studi Sarjana Kedokteran, Fakultas Kedokteran, Universitas Andalas, Padang, Indonesia Author
Kanaya Syafa Amanda Program Studi Sarjana Kedokteran, Fakultas Kedokteran, Universitas Andalas, Padang, Indonesia Author
Athaillah Faiz Assyawal Program Studi Sarjana Kedokteran, Fakultas Kedokteran, Universitas Andalas, Padang, Indonesia Author
Sultan Kemal Dewantara Program Studi Sarjana Kedokteran, Fakultas Kedokteran, Universitas Andalas, Padang, Indonesia Author
Arvando Yoga Pratama Program Studi Sarjana Kedokteran, Fakultas Kedokteran, Universitas Andalas, Padang, Indonesia Author
Nabil Abdillah Al Afif Suma Program Studi Sarjana Kedokteran, Fakultas Kedokteran, Universitas Andalas, Padang, Indonesia Author

DOI:

https://doi.org/10.62710/fqs4jw22

Keywords:

Diabetic Kidney Disease, Exosomes, NLRP3 Inflammasome, Podocytes, Pyroptosis

Abstract

Diabetic kidney disease (DKD) is triggered by hyperglycemia, oxidative stress, and chronic inflammation, while NLRP3 inflammasome activation induces pyroptosis in podocytes and kidney cells. Conventional therapies cannot halt this progression, so exosome-based therapy has emerged as a cell-free alternative. To evaluate exosome sources, molecular cargo, mechanisms, and therapeutic outcomes of NLRP3 inhibition in DKD models. This PRISMA 2020-based systematic review searched PubMed and ScienceDirect for English-language studies published within the last five years. Included studies used in vivo DKD models, alone or combined with in vitro experiments, and evaluated exosome-mediated regulation of the NLRP3 pathway. Five of 184 records were synthesized narratively. All studies used diabetic nephropathy mouse models. Exosomes from mesenchymal stem cells (four studies) and M2 macrophages (one study) carried miR-22-3p, miR-30a-5p, miR-30e-5p, SBF2-AS1, or ZHX2. These molecules suppressed NLRP3 directly or through ELAVL1, AGEs/RAGE, and NEK7, reduced caspase-1 activation, GSDMD-N cleavage, and IL-1β and IL-18 release (p<0.05), and protected podocytes. Exosome-based therapy inhibits NLRP3-mediated pyroptosis in experimental DKD, but its clinical application still requires safety testing, standardized production, and human studies.

Downloads

Download data is not yet available.

References

Chen, W., Liu, J., Zou, Y., Lu, F., Zhang, J., Hu, Y., et al. (2025). O-GlcNAcylation stabilizes NEK7 to drive podocyte pyroptosis in diabetic kidney disease. Diabetes, 74(12), 2279–2290.

Chronic kidney disease and risk management: Standards of care in diabetes—2024. (2024). Diabetes Care, 47(Suppl. 1), S219–S230.

Frank, D., & Vince, J. E. (2019). Pyroptosis versus necroptosis: Similarities, differences, and crosstalk. Cell Death & Differentiation, 26(1), 99–114.

Galicia-Garcia, U., Benito-Vicente, A., Jebari, S., Larrea-Sebal, A., Siddiqi, H., Uribe, K. B., et al. (2020). Pathophysiology of type 2 diabetes mellitus. International Journal of Molecular Sciences, 21(17), Article 6275.

Green, J. B., Mottl, A. K., Bakris, G., Heerspink, H. J. L., Mann, J. F. E., McGill, J. B., et al. (2023). Design of the COmbinatioN effect of FInerenone anD EmpaglifloziN in participants with chronic kidney disease and type 2 diabetes using a UACR Endpoint study (CONFIDENCE). Nephrology Dialysis Transplantation, 38(4), 894–903.

Guerrero-Mauvecin, J., Villar-Gómez, N., Rayego-Mateos, S., Ramos, A. M., Ruiz-Ortega, M., Ortiz, A., et al. (2023). Regulated necrosis role in inflammation and repair in acute kidney injury. Frontiers in Immunology, 14, Article 1324996.

Gupta, A., Singh, K., Fatima, S., Ambreen, S., Zimmermann, S., Younis, R., et al. (2022). Neutrophil extracellular traps promote NLRP3 inflammasome activation and glomerular endothelial dysfunction in diabetic kidney disease. Nutrients, 14(14), Article 2965.

Haraguchi, R., Kohara, Y., Matsubayashi, K., Kitazawa, R., & Kitazawa, S. (2020). New insights into the pathogenesis of diabetic nephropathy: Proximal renal tubules are primary target of oxidative stress in diabetic kidney. Acta Histochemica et Cytochemica, 53(2), 21–31.

Hossain, M. J., Al-Mamun, M., & Islam, M. R. (2024). Diabetes mellitus, the fastest growing global public health concern: Early detection should be focused. Health Science Reports, 7(3), Article e2004.

Jiao, X., & Tian, G. (2025). Role of the NLRP3 inflammasome in diabetes and its complications (Review). Molecular Medicine Reports, 32(5), Article 292.

KDIGO 2022 clinical practice guideline for diabetes management in chronic kidney disease. (2022). Kidney International, 102(5S), S1–S127.

Lu, W., Guo, K., Xi, D., & Xia, Z. (2023). Exosomal miR-30a-5p targets NLRP3 to suppress podocyte pyroptosis in diabetic nephropathy. BIOCELL, 47(9), 1995–2008.

Lv, J., Hao, Y. N., Wang, X. P., Lu, W. H., Xie, L. Y., & Niu, D. (2023). Bone marrow mesenchymal stem cell-derived exosomal miR-30e-5p ameliorates high-glucose induced renal proximal tubular cell pyroptosis by inhibiting ELAVL1. Renal Failure, 45(1).

Mathur, A., Pandey, V. K., Khan, M. F., & Kakkar, P. (2021). PHLPP1/Nrf2-Mdm2 axis induces renal apoptosis via influencing nucleo-cytoplasmic shuttling of FoxO1 during diabetic nephropathy. Molecular and Cellular Biochemistry, 476(10), 3681–3699.

Ong, K. L., Stafford, L. K., McLaughlin, S. A., Boyko, E. J., Vollset, S. E., Smith, A. E., et al. (2023). Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: A systematic analysis for the Global Burden of Disease Study 2021. The Lancet, 402(10397), 203–234.

Sahakyan, G., Vejux, A., & Sahakyan, N. (2022). The role of oxidative stress-mediated inflammation in the development of T2DM-induced diabetic nephropathy: Possible preventive action of tannins and other oligomeric polyphenols. Molecules, 27(24), Article 9035.

Saito, R., Rocanin-Arjo, A., You, Y. H., Darshi, M., Van Espen, B., Miyamoto, S., et al. (2016). Systems biology analysis reveals role of MDM2 in diabetic nephropathy. JCI Insight, 1(17).

Varda, L., Vreča, N., Ekart, R., Bevc, S., & Piko, N. (2026). Diabetic kidney disease: From pathophysiology to treatment perspectives. Kidney and Blood Pressure Research, 51(1), Article 107.

Wan, J., Liu, D., Pan, S., Zhou, S., & Liu, Z. (2022). NLRP3-mediated pyroptosis in diabetic nephropathy. Frontiers in Pharmacology, 13, Article 998574.

Wang, S., Cai, X., Weng, C., Su, M., Yang, Q., Chen, B., et al. (2026). GMSCs-derived exosome ZHX2 improves diabetes nephropathy by blocking AGEs/RAGE/NLRP3 pathway to inhibit podocyte pyroptosis and inflammatory response. FASEB Journal, 40(2).

Wang, Y., Liu, J., Wang, H., Lv, S., Liu, Q., Li, S., et al. (2023). Mesenchymal stem cell-derived exosomes ameliorate diabetic kidney disease through the NLRP3 signaling pathway. Stem Cells, 41(4), 368–383.

Zhang, Y., Zhan, Q., Zhao, M., Liu, H., & Huang, H. (2026). M2 macrophage exosomal SBF2-AS1 suppresses NLRP3-mediated pyroptosis to ameliorate high glucose-induced podocyte injury through the miR-650/MDM2/NEK7 axis. Cellular Signalling, 147, Article 112752.

Zheng, Y., Ley, S. H., & Hu, F. B. (2018). Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nature Reviews Endocrinology, 14(2), 88–98.