Immunomodulatory Nanozymes Eradicate Intracellular Infections and Rescue Immunoparalysis for Treating Multidrug-Resistant Bacterial Sepsis

Abstract

Sepsis and their sequelae are the leading causes of death in intensive care units, with limited therapeutic options. Immunoparalysis plays a vital role in the pathophysiological progression of sepsis, leading to intracellular persistent infections and high mortality of septic patients. Eradicating intracellular infections and rescuing immunoparalysis are critical for sepsis management, yet effective tactics remain elusive. Here, we report immunomodulatory nanozymes (named PdIr@OMVs) that enable intracellular bacteria elimination and reinvigorate systemic innate-adaptive immune response during immunoparalysis to tackle multidrug-resistant (MDR) bacterial sepsis. The PdIr@OMVs are designed by encapsulating plasmonic PdIr nanocatalysts with immunostimulants of biocompatible bacterial outer membrane vesicles (OMVs). PdIr@OMVs exhibit unique localized surface plasmon response-enhanced peroxidase-like catalytic activity, and inherit the remarkable immunocyte-targeting capability and adjuvanticity of OMVs. We demonstrate that PdIr@OMVs not only potentiate the phagolysosomal killing effect of impaired macrophages via in situ catalysis to eradicate intracellular MDR bacteria and burst antigen release, but also allow rapid activation/maturation of dendritic cells to boost the presentation of bacterial antigen and orchestrate innate-adaptive immunity for rescuing immunoparalysis. In two immunocompromised mouse models of MDR bacterial sepsis, PdIr@OMVs collaboratively reduce bacterial burden and restore immune homeostasis, thereby circumventing organ damage and enabling the recovery of septic mice. Our work offers a promising therapeutic modality for sepsis and septic shock.

Keywords

bacterial infections / immunosuppression / multidrug resistance / nanozymes / sepsis

References

[1] M. Cecconi, L. Evans, M. Levy, and A. Rhodes, “Sepsis and Septic Shock,” Lancet392 (2018): 75-87.

[2] R. C. Keskey, J. Xiao, S. Hyoju, et al., “Enterobactin Inhibits Microbiota-Dpendent Activation of AhR to Promote Bacterial Sepsis in Mice,” Nature Microbiology10 (2025): 388-404.

[3] C. W. Seymour, F. Gesten, H. C. Prescott, et al., “Time to Treatment and Mortality during Mandated Emergency Care for Sepsis,” New England Journal of Medicine376 (2017): 2235-2244.

[4] D. Liu, S. Y. Huang, J. H. Sun, et al., “Sepsis-Induced Immunosuppression: Mechanisms, Diagnosis and Current Treatment Options,” Military Medical Research9 (2022): 56.

[5] D. P. Schrijver, R. J. Roring, J. Dechers, et al., “Resolving Sepsis-Induced Immunoparalysis via Trained Immunity by Targeting Interleukin-4 to Myeloid Cells,” Nature Biomedical Engineering7 (2023): 1097-1112.

[6] C. M. Padovani and K. Yin, “Immunosuppression in Sepsis: Biomarkers and Specialized Pro-Resolving Mediators,” Biomedicines12 (2024): 175.

[7] T. van der Poll, “Immunotherapy of Sepsis,” The Lancet Infectious Diseases1 (2001): 165-174.

[8] B. Novakovic, E. Habibi, S. Y. Wang, et al., “β-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance,” Cell167 (2016): 1354-1368.e14.

[9] K. C. Chang, C. A. Burnham, S. M. Compton, et al., “Blockade of the Negative Co-Stimulatory Molecules PD-1 and CTLA-4 Improves Survival in Primary and Secondary Fungal Sepsis,” Critical Care (London, England)17 (2013): R85.

[10] J. J. Presneill, T. Harris, A. G. Stewart, J. F. Cade, and J. W. Wilson, “A Randomized Phase II Trial of Granulocyte-Macrophage Colony-Stimulating Factor Therapy in Severe Sepsis With Respiratory Dysfunction,” American Journal of Respiratory and Critical Care Medicine166 (2002): 138-143.

[11] L. Bo, F. Wang, J. Zhu, J. Li, and X. Deng, “Granulocyte-Colony Stimulating Factor (G-CSF) and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) for Sepsis: A Meta-Analysis,” Critical Care (London, England)15 (2011): R58.

[12] W. D. Docke, F. Randow, U. Syrbe, et al., “Monocyte Deactivation in Septic Patients: Restoration by IFN-γ Treatment,” Nature Medicine3 (1997): 678-681.

[13] Z. Li, S. Zhang, Z. Fu, et al., “Surficial Nano-Deposition Locoregionally Yielding Bactericidal Super CAR-Macrophages Expedites Periprosthetic Osseointegration,” Science Advances9 (2023): eadg3365.

[14] J. L. Wang, Y. Chen, J. X. Song, et al., “Aggregation-Induced Emission Photosensitizer-Armored Magnetic Nanoparticles for Sepsis Treatment: Combating Multidrug-Resistant Bacteria and Alleviating Inflammation,” Advanced Functional Materials34 (2024): 2312162.

[15] X. Du, M. Zhang, H. Zhou, et al., “Decoy Nanozymes Enable Multitarget Blockade of Proinflammatory Cascades for the Treatment of Multi-Drug-Resistant Bacterial Sepsis,” Research2022 (2022): 9767643.

[16] R. S. Flannagan, V. Jaumouille, S. Grinstein, A. K. Abbas, S. J. Galli, and P. M. Howley, “The Cell Biology of Phagocytosis,” Annual Review of Pathology7 (2012): 61-98.

[17] X. Huang, F. Venet, Y. L. Wang, et al., “PD-1 Expression by Macrophages Plays a Pathologic Role in Altering Microbial Clearance and the Innate Inflammatory Response to Sepsis,” Proceedings National Academy of Science of the United States of America106 (2009): 6303-6308.

[18] X. Yang, Y. Yin, X. Yan, Z. Yu, Y. Liu, and J. Cao, “Flagellin Attenuates Experimental Sepsis in a Macrophage-Dependent Manner,” Critical Care (London, England)23 (2019): 106.

[19] Y. Wang, B. Tang, H. Li, et al., “A Small-Molecule Inhibitor of Keap1-Nrf2 Interaction Attenuates Sepsis by Selectively Augmenting the Antibacterial Defence of Macrophages at Infection Sites,” eBioMedicine90 (2023): 104480.

[20] X. Hou, X. Zhang, W. Zhao, et al., “Vitamin Lipid Nanoparticles Enable Adoptive Macrophage Transfer for the Treatment of Multidrug-Resistant Bacterial Sepsis,” Nature Nanotechnology15 (2020): 41-46.

[21] H. Cao, Y. Gao, H. Jia, et al., “Macrophage-Membrane-Camouflaged Nonviral Gene Vectors for the Treatment of Multidrug-Resistant Bacterial Sepsis,” Nano Letters22 (2022): 7882-7891.

[22] Q. Zhao, Z. Gong, J. Wang, et al., “A Zinc- and Calcium-Rich Lysosomal Nanoreactor Rescues Monocyte/Macrophage Dysfunction Under Sepsis,” Advancement of Science10 (2023): 2205097.

[23] L. Ma, J. J. Zheng, N. Zhou, et al., “A Natural Biogenic Nanozyme for Scavenging Superoxide Radicals,” Nature Communications15 (2024): 233.

[24] Z. Li, G. Jia, Z. Su, and C. Zhu, “Nanozyme-Based Strategies Against Bone Infection,” Research8 (2025): 0605.

[25] J. Yang, R. Zhang, H. Zhao, et al., “Bioinspired Copper Single-Atom Nanozyme as a Superoxide Dismutase-Like Antioxidant for Sepsis Treatment,” Exploration2 (2022): 20210267.

[26] S. Wang and K. Qi, “Localized Surface Plasmon Resonance Effect in S-Scheme Photocatalyst,” Journal of Materials Science and Technology226 (2025): 317-319.

[27] L. P. Jahromi and G. Fuhrmann, “Bacterial Extracellular Vesicles: Understanding Biology Promotes Applications as Nanopharmaceuticals,” Drug Delivery Reviews173 (2021): 125-140.

[28] Q. Cheng, G. Niu, Y. He, et al., “Innovative Design of Bacterial Outer Membrane Vesicles for Vaccine Development,” Nano Today61 (2025): 102650.

[29] C. Ding, R. He, T. Cheng, et al., “Bacterial Outer Membrane-Based Biomimetic Immune Adaptors: Mild Immunomodulatory and Bacterial Targeted Delivery Strategy Against Implant-Related Infections,” Advanced Functional Materials33 (2023): 2304168.

[30] T. Cai, G. Fang, X. Tian, J. J. Yin, C. Chen, and C. Ge, “Optimization of Antibacterial Efficacy of Noble-Metal-Based Core-Shell Nanostructures and Effect of Natural Organic Matter,” ACS Nano13 (2019): 12694-12702.

[31] X. Xia, L. Figueroa-Cosme, J. Tao, et al., “Facile Synthesis of Iridium Nanocrystals With Well-Controlled Facets Using Seed-Mediated Growth,” Journal of the American Chemical Society136 (2014): 10878-10881.

[32] Y. He, S. Zhang, Y. She, et al., “Innovative Utilization of Cell Membrane-Coated Nanoparticles in Precision Cancer Therapy,” Exploration4 (2024): 20230164.

[33] Y. Wu, G. Deng, Z. Song, et al., “Enhancing Antibacterial Immunotherapy for Bacterial Pneumonia via Nanovaccines Coated With Outer Membrane Vesicles,” Chemical Engineering Journal436 (2022): 135040.

[34] S. Qing, C. Lyu, L. Zhu, et al., “Biomineralized Bacterial Outer Membrane Vesicles Potentiate Safe and Efficient Tumor Microenvironment Reprogramming for Anticancer Therapy,” Advanced Materials32 (2020): 2002085.

[35] J. Thoma, S. Manioglu, D. Kalbermatter, P. D. Bosshart, D. Fotiadis, and D. J. Muller, “Protein-Enriched Outer Membrane Vesicles as a Native Platform for Outer Membrane Protein Studies,” Communications Biology1 (2018): 23.

[36] X. Geng, X. Du, W. Wang, et al., “Confined Cascade Metabolic Reprogramming Nanoreactor for Targeted Alcohol Detoxification and Alcoholic Liver Injury Management,” ACS Nano17 (2023): 7443-7455.

[37] X. Xia, J. Zhang, N. Lu, et al., “Pd-Ir Core-Shell Nanocubes: A Type of Highly Efficient and Versatile Peroxidase Mimic,” ACS Nano9 (2015): 9994-10004.

[38] J. Bai, Y. Feng, W. Li, et al., “Alternative Copper-Based Single-Atom Nanozyme With Superior Multienzyme Activities and NIR-II Responsiveness to Fight Against Deep Tissue Infections,” Research6 (2023): 0031.

[39] X. Du, B. Jia, W. Wang, et al., “pH-Switchable Nanozyme Cascade Catalysis: A Strategy for Spatial-Temporal Modulation of Pathological Wound Microenvironment to Rescue Stalled Healing in Diabetic Ulcer,” Journal of Nanbiotechnology20 (2022): 12.

[40] X. Zhao, T. Yang, D. Wang, et al., “Gold Nanorods/Metal-Organic Framework Hybrids: Photo-Enhanced Peroxidase-Like Activity and SERS Performance for Organic Dyestuff Degradation and Detection,” Analytical Chemistry94 (2022): 4484-4494.

[41] T. Shang, D. Xiao, F. Meng, et al., “Real-Space Measurement of Orbital Electron Populations for Li_1-xCoO₂,” Nature Communications13 (2022): 5810.

[42] G. Xu, X. Du, W. Wang, et al., “Plasmonic Nanozymes: Leveraging Localized Surface Plasmon Resonance to Boost the Enzyme-Mimicking Activity of Nanomaterials,” Small18 (2022): 2204131.

[43] Y. Rao, G. Xu, Z. Zhang, et al., “Coupling Doping and Localized Surface Plasmon Resonance Toward Acidic pH-Preferential Catalase-Like Nanozyme for Oxygen-Dominated Synergistic Cancer Therapy,” Chemical Engineering Journal465 (2023): 142961.

[44] L. Feng, S. Gai, F. He, P. Yang, and Y Zhao, “Multifunctional Bismuth Ferrite Nanocatalysts With Optical and Magnetic Functions for Ultrasound-Enhanced Tumor Theranostics,” ACS Nano14 (2020): 7245-7258.

[45] W. Gao, J. He, L. Chen, et al., “Deciphering the Catalytic Mechanism of Superoxide Dismutase Activity of Carbon Dot Nanozyme,” Nature Communications14 (2023): 160.

[46] T. Freese, J. T. Meijer, B. L. Feringa, and S. B Beil, “An Organic Perspective on Photocatalytic Production of Hydrogen Peroxide,” Nature Catalysis6 (2023): 553-558.

[47] X. Peng, D. Li, J. Zhu, J. Cheng, and G Liu, “Beyond Antibiotics: Photo/Sonodynamic Approaches for Bacterial Theranostics,” Nano-Micro Lett12 (2020): 144.

[48] Y. Zhang, X. Xie, W. Ma, et al., “Multi-targeted Antisense Oligonucleotide Delivery by a Framework Nucleic Acid for Inhibiting Biofilm Formation and Virulence,” Nano-Micro Letters12 (2020): 74.

[49] W. Feng, G. Li, X. Kang, et al., “Cascade-Targeting Poly(Amino Acid) Nanoparticles Eliminate Intracellular Bacteria via On-Site Antibiotic Delivery,” Advanced Materials34 (2022): 2109789.

[50] J. Zhou, R. Chang, B. Wei, et al., “Photothermal Nano-Vaccine Promoting Antigen Presentation and Dendritic Cells Infiltration for Enhanced Immunotherapy of Melanoma via Transdermal Microneedles Delivery,” Research2022 (2022): 9816272.

[51] S. L. Gaytan, E. Beaven, S. S. Gadad, and M Nurunnabi, “Progress and Prospect of Nanotechnology for Cardiac Fibrosis Treatment,” Interdisciplinary Medicine1 (2023): e20230018.

[52] M. Chen, Y. Sun, and H Liu, “Cell Membrane Biomimetic Nanomedicines for Cancer Phototherapy,” Interdisciplinary Medicine1 (2023): e20220012.

[53] S. Manepalli, J. A. Gandhi, V. V. Ekhar, M. B. Asplund, C. Coelho, and L. R Martinez, “Characterization of a Cyclophosphamide-Induced Murine Model of Immunosuppression to Study Acinetobacter baumannii Pathogenesis,” Journal of Medical Microbiology62 (2014): 1747-1754.

[54] A. Kasuga, T. Maruyama, I. Takei, et al., “The Role of Cytotoxic Macrophages in Non-Obese Diabetic Mice: Cytotoxicity Against Murine Mastocytoma and Beta-Cell Lines,” Diabetologia36 (1993): 1252-1257.

[55] M. Ye, Y. Zhao, Y. Wang, et al., “NAD(H)-Loaded Nanoparticles for Efficient Sepsis Therapy via Modulating Immune and Vascular Homeostasis,” Nature Nanotechnology17 (2022): 880-890.

[56] G. Kresse and J Furthmuller, “Efficiency of Ab-Initio Total Energy Calculations for Metals and Semiconductors Using a Plane-Wave Basis Set,” Computation Materials Science6 (1996): 15-50.

[57] J. P. Perdew, K. Burke, and M Ernzerhof, “Generalized Gradient Approximation Made Simple,” Physical Review Letter77 (1996): 3865-3868.

[58] S. Grimme, J. Antony, S. Ehrlich, and H Krieg, “A Consistent and Accurate Ab Initio Parametrization of Density Functional Dispersion Correction (DFT-D) for the 94 Elements H-Pu,” Journal of Chemical Physics132 (2010): 154104.

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2025 The Author(s). Exploration published by Henan University and John Wiley & Sons Australia, Ltd.