journal article·2022-08Open access

NAD(H)-loaded nanoparticles for efficient sepsis therapy via modulating immune and vascular homeostasis

Mingzhou Ye, Yi Zhao, Yuyuan Wang, Ruosen Xie, Yao Tong, John-Demian Sauer, Shaoqin Gong

Nature Nanotechnology· Volume 17· Issue 8

Abstract

Sepsis is a life-threatening organ dysfunction responsible for nearly 270,000 deaths annually in the United States alone. Nicotinamide adenine dinucleotide (NAD+), an immunomodulator, can potentially treat sepsis; however, clinical application of NAD+ is hindered by its inability to be directly taken up by cells. To address this challenge, a family of nanoparticles (NPs) loaded with either NAD+ or the reduced form of NAD+ (NADH), hereafter NAD(H)-loaded NPs, were engineered to enable direct cellular transport and replenishment of NAD(H). The NAD(H)-loaded NPs improved cellular energy supply, suppressed inflammation and prevented inflammation-induced cell pyroptosis and apoptosis. Therefore, the NPs can help maintain immune homoeostasis and vascular function, two key factors in the pathogenesis of sepsis. The NAD(H)-loaded NPs demonstrated excellent therapeutic efficacies in treating endotoxemia and multidrug-resistant pathogen-induced bacteremia. In addition, the NAD(H)-loaded NPs prevented caecal ligation and puncture-induced multiorgan injury and improved outcomes of secondary Pseudomonas aeruginosa infections following caecal ligation and puncture, thus potentially leading to a highly innovative and translational approach to treat sepsis efficiently and safely.
Source: europepmc · Quality: candidate unverified · Source record ↗

Research context

OpenAlex topics: Neonatal and Maternal Infections · Immune Response and Inflammation · Inflammasome and immune disorders

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

References (53)

Show source-provided references
1. Rudd, K. E. et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet 395, 200–211 (2020).10.1016/S0140-6736(19)32989-7 ↗
2. Dugar, S., Choudhary, C. & Duggal, A. Sepsis and septic shock: guideline-based management. Clevel. Clin. J. Med. 87, 53–64 (2020).10.3949/ccjm.87a.18143 ↗
3. Rhodes, A. et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 43, 304–377 (2017).10.1007/s00134-017-4683-6 ↗
4. Grahnert, A. et al. NAD+: a modulator of immune functions. Innate Immun. 17, 212–233 (2011).10.1177/1753425910361989 ↗
5. Hong, G. et al. Administration of nicotinamide riboside prevents oxidative stress and organ injury in sepsis. Free Radic. Biol. Med. 123, 125–137 (2018).10.1016/j.freeradbiomed.2018.05.073 ↗
6. Nadlinger, K., Birkmayer, J., Gebauer, F. & Kunze, R. Influence of reduced nicotinamide adenine dinucleotide on the production of interleukin-6 by peripheral human blood leukocytes. Neuroimmunomodulation 9, 203–208 (2001).10.1159/000049027 ↗
7. Van Gool, F. et al. Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner. Nat. Med. 15, 206–210 (2009).10.1038/nm.1906 ↗
8. Gerner, R. R. et al. NAD metabolism fuels human and mouse intestinal inflammation. Gut 67, 1813–1823 (2018).10.1136/gutjnl-2017-314241 ↗
9. Iske, J. et al. NAD+ prevents septic shock by non-canonical inflammasome blockade and IL-10. Preprint at bioRxiv https://doi.org/10.1101/2020.03.29.013649 (2020).10.1101/2020.03.29.013649 ↗
10. Biefer, H. R. C. et al. Mast cells regulate CD4+ T-cell differentiation in the absence of antigen presentation. J. Allergy Clin. Immunol. 142, 1894–1908.E7 (2018).10.1016/j.jaci.2018.01.038 ↗
11. Dongsheng, W., Sili, Z., Minghe, C. & Chaoyu, M. Effect of nicotinamide mononucleotide on mortality of mice with endotoxic shock. J. Pharm. Pract. 39, 134–137 (2021).
12. Cantó, C., Menzies, K. J. & Auwerx, J. NAD+ metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab. 22, 31–53 (2015).10.1016/j.cmet.2015.05.023 ↗
13. Ratajczak, J. et al. NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nat. Commun. 7, 13103 (2016).10.1038/ncomms13103 ↗
14. Chong, Z.-Z., Lin, S.-H., Li, F. & Maiese, K. The sirtuin inhibitor nicotinamide enhances neuronal cell survival during acute anoxic injury through AKT, BAD, PARP, and mitochondrial associated. Curr. Neurovascular Res. 2, 271–285 (2005).10.2174/156720205774322584 ↗
15. Klaidman, L. et al. Nicotinamide offers multiple protective mechanisms in stroke as a precursor for NAD+, as a PARP inhibitor and by partial restoration of mitochondrial function. Pharmacology 69, 150–157 (2003).10.1159/000072668 ↗
16. Chen, H. et al. NAD+-carrying mesoporous silica nanoparticles can prevent oxidative stress-induced energy failures of both rodent astrocytes and PC12 cells. PLoS One 8, e74100 (2013).10.1371/journal.pone.0074100 ↗
17. Han, Y. Y. et al. Liposomal ATP or NAD+ protects human endothelial cells from energy failure in a cell culture model of sepsis. Res. Commun. Mol. Pathol. Pharmacol. 110, 107–116 (2001).
18. Remick, D. G. Pathophysiology of sepsis. Am. J. Pathol. 170, 1435–1444 (2007).10.2353/ajpath.2007.060872 ↗
19. Crowley, C., Payne, C., Bernstein, H., Bernstein, C. & Roe, D. The NAD+ precursors, nicotinic acid and nicotinamide protect cells against apoptosis induced by a multiple stress inducer, deoxycholate. Cell Death Differ. 7, 314–326 (2000).10.1038/sj.cdd.4400658 ↗
20. Li, J., Yang, Y. & Huang, L. Calcium phosphate nanoparticles with an asymmetric lipid bilayer coating for siRNA delivery to the tumor. J. Controlled Release 158, 108–114 (2012).10.1016/j.jconrel.2011.10.020 ↗
21. Li, J., Chen, Y.-C., Tseng, Y.-C., Mozumdar, S. & Huang, L. Biodegradable calcium phosphate nanoparticle with lipid coating for systemic siRNA delivery. J. Controlled Release 142, 416–421 (2010).10.1016/j.jconrel.2009.11.008 ↗
22. Yang, H. et al. Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell 130, 1095–1107 (2007).10.1016/j.cell.2007.07.035 ↗
23. Zapata‐Pérez, R., Wanders, R. J., van Karnebeek, C. D. & Houtkooper, R. H. NAD+ homeostasis in human health and disease. EMBO Mol. Med. 13, e13943 (2021).10.15252/emmm.202113943 ↗
24. Cameron, A. M. et al. Inflammatory macrophage dependence on NAD+ salvage is a consequence of reactive oxygen species–mediated DNA damage. Nat. Immunol. 20, 420–432 (2019).10.1038/s41590-019-0336-y ↗
25. Weiss, R. et al. Nicotinamide: a vitamin able to shift macrophage differentiation toward macrophages with restricted inflammatory features. Innate Immun. 21, 813–826 (2015).10.1177/1753425915602545 ↗
26. Henry, B. D. et al. Engineered liposomes sequester bacterial exotoxins and protect from severe invasive infections in mice. Nat. Biotechnol. 33, 81–88 (2015).10.1038/nbt.3037 ↗
27. Martínez-García, J. J. et al. P2X7 receptor induces mitochondrial failure in monocytes and compromises NLRP3 inflammasome activation during sepsis. Nat. Commun. 10, 2711 (2019).10.1038/s41467-019-10626-x ↗
28. Hagar, J. A., Powell, D. A., Aachoui, Y., Ernst, R. K. & Miao, E. A. Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 341, 1250–1253 (2013).10.1126/science.1240988 ↗
29. Kayagaki, N. et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666–671 (2015).10.1038/nature15541 ↗
30. Dempsey, L. A. Sirtuin regulation of NLRP3. Nat. Immunol. 21, 358–358 (2020).
31. Hotchkiss, R. S., Monneret, G. & Payen, D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat. Rev. Immunol. 13, 862–874 (2013).10.1038/nri3552 ↗
32. Wendel, M. & Heller, A. R. Mitochondrial function and dysfunction in sepsis. Wien. Medizinische Wochenschr. 160, 118–123 (2010).10.1007/s10354-010-0766-5 ↗
33. Lupu, F., Kinasewitz, G. & Dormer, K. The role of endothelial shear stress on haemodynamics, inflammation, coagulation and glycocalyx during sepsis. J. Cell. Mol. Med. 24, 12258–12271 (2020).10.1111/jcmm.15895 ↗
34. Polacheck, W. J. et al. A non-canonical Notch complex regulates adherens junctions and vascular barrier function. Nature 552, 258–262 (2017).10.1038/nature24998 ↗
35. Szekanecz, Z., Szamosi, S., Kovács, G. E., Kocsis, E. & Benkő, S. The NLRP3 inflammasome-interleukin 1 pathway as a therapeutic target in gout. Arch. Biochem. Biophys. 670, 82–93 (2019).10.1016/j.abb.2019.01.031 ↗
36. Caraballo, C. & Jaimes, F. Organ dysfunction in sepsis: an ominous trajectory from infection to death. Yale J. Biol. Med. 92, 629–640 (2019).
37. Venet, F. & Monneret, G. Advances in the understanding and treatment of sepsis-induced immunosuppression. Nat. Rev. Nephrol. 14, 121–137 (2018).10.1038/nrneph.2017.165 ↗
38. Darnifayanti, D., Tjipta, G. D., Rusdidjas, R. & Lubis, B. M. Immature-to-total neutrophil ratio as an early diagnostic tool of bacterial neonatal sepsis. Paediatr. Indones. 55, 153–157 (2015).10.14238/pi55.3.2015.153-7 ↗
39. Zhu, Y. G. et al. Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin- induced acute lung injury in mice. Stem Cells 32, 116–125 (2014).10.1002/stem.1504 ↗
40. Ataide, M. A. et al. Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection. PLoS Pathog. 10, e1003885 (2014).10.1371/journal.ppat.1003885 ↗
41. Arienti, S., Barth, N. D., Dorward, D. A., Rossi, A. G. & Dransfield, I. Regulation of apoptotic cell clearance during resolution of inflammation. Front. Pharmacol. https://doi.org/10.3389/fphar.2019.00891 (2019).10.3389/fphar.2019.00891 ↗
42. Prescott, H. C. & Angus, D. C. Enhancing recovery from sepsis: a review. JAMA 319, 62–75 (2018).10.1001/jama.2017.17687 ↗
43. Shang, S. et al. Artesunate interacts with the vitamin D receptor to reverse sepsis‐induced immunosuppression in a mouse model via enhancing autophagy. Br. J. Pharmacol. 177, 4147–4165 (2020).10.1111/bph.15158 ↗
44. Nascimento, D. C. et al. Role of regulatory T cells in long-term immune dysfunction associated with severe sepsis. Crit. Care Med. 38, 1718–1725 (2010).10.1097/CCM.0b013e3181e78ad0 ↗
45. Grailer, J. J., Kalbitz, M., Zetoune, F. S. & Ward, P. A. Persistent neutrophil dysfunction and suppression of acute lung injury in mice following cecal ligation and puncture sepsis. J. Innate Immun. 6, 695–705 (2014).10.1159/000362554 ↗
46. Pugh, A. M., Auteri, N. J., Goetzman, H. S., Caldwell, C. C. & Nomellini, V. A murine model of persistent inflammation, immune suppression, and catabolism syndrome. Int. J. Mol. Sci. 18, 1741 (2017).10.3390/ijms18081741 ↗
47. Ye, M. et al. A dual‐responsive antibiotic‐loaded nanoparticle specifically binds pathogens and overcomes antimicrobial‐resistant infections. Adv. Mater. 33, 2006772 (2021).10.1002/adma.202006772 ↗
48. Butler, K. S., Peeler, D. J., Casey, B. J., Dair, B. J. & Elespuru, R. K. Silver nanoparticles: correlating nanoparticle size and cellular uptake with genotoxicity. Mutagenesis 30, 577–591 (2015).10.1093/mutage/gev020 ↗
49. Sendler, M. et al. Cathepsin B-mediated activation of trypsinogen in endocytosing macrophages increases severity of pancreatitis in mice. Gastroenterology 154, 704–718.E10 (2018).10.1053/j.gastro.2017.10.018 ↗
50. Vong, L., Sherman, P. M. & Glogauer, M. in Mouse Models of Innate Immunity (ed. Allen, I. C.) 41–50 (Springer, 2013).10.1007/978-1-62703-481-4_5 ↗
51. Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔC_T method. Methods 25, 402–408 (2001).10.1006/meth.2001.1262 ↗
52. Dawulieti, J. et al. Treatment of severe sepsis with nanoparticulate cell-free DNA scavengers. Sci. Adv. 6, eaay7148 (2020).10.1126/sciadv.aay7148 ↗
53. Shrum, B. et al. A robust scoring system to evaluate sepsis severity in an animal model. BMC Res. Notes 7, 233 (2014).10.1186/1756-0500-7-233 ↗