Hee Ho Park^‡, Wooram Park^‡, Yun Young Lee^‡, Hyelim Kim, Hee Seung Seo, Dong Wook Choi, Ho-Keun Kwon, Dong Hee Na, Tae-Hyung Kim, Young Bin Choy, June Hong Ahn^*, Wonhwa Lee^*, Chun Gwon Park^*

Prof. H. H. P
Department of Biotechnology and Bioengineering, Kangwon National University, Chuncheon, Gangwon-do 24341, Republic of Korea

Prof. W. P
Department of Biomedical-Chemical Engineering, The Catholic University of Korea, Bucheon, 14662, Republic of Korea

Y. Y. L and Prof. Y. B. C
Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul 03080, Republic of Korea

H. K
College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea

H. S. S
Department of Biomedical Engineering, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), Suwon, 16419, Republic of Korea

Dr. D. W. C
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA

Prof. H.-K. K
Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul 03722, Korea

Prof. D.H. N
College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea

Prof. T.-H. K
School of Integrative Engineering, Chung-Ang University, Seoul 06974, Republic of Korea

Prof. J. H. A
Division of Pulmonology and Allergy, Department of Internal Medicine, College of Medicine, Yeungnam University and Regional Center for Respiratory Diseases, Yeungnam University Medical Center, Daegu, 42415, Republic of Korea

Dr. W. L.
Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141 Republic of Korea

Prof. C. G. P
Department of Biomedical Engineering, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), Suwon, Republic of Korea Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, 2066 Seoburo, Jangan-gu, Suwon 16419, Republic of Korea

The current outbreak of the beta‐coronavirus (beta‐Cov) severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) began in December 2019. No specific antiviral treatments or vaccines are currently available. A recent study has reported that coronavirus disease 2019 (COVID‐19), the disease caused by SARS‐CoV‐2 infection, is associated with neutrophil‐specific plasma membrane rupture, and release excessive neutrophil extracellular traps (NETs) and extracellular DNAs (eDNAs). This mechanism involves the activation of NETosis, a neutrophil‐specific programmed cell death, which is believed to play a crucial role in COVID‐19 pathogenesis. Further progression of the disease can cause uncontrolled inflammation, leading to the initiation of cytokine storms, acute respiratory distress syndrome (ARDS), and sepsis. Herein, it is reported that DNase‐I‐coated melanin‐like nanospheres (DNase‐I pMNSs) mitigate sepsis‐associated NETosis dysregulation, thereby preventing further progression of the disease. Recombinant DNase‐I and poly(ethylene glycol) (PEG) are used as coatings to promote the lengthy circulation and dissolution of NET structure. The data indicate that the application of bioinspired DNase‐I pMNSs reduce neutrophil counts and NETosis‐related factors in the plasma of SARS‐CoV‐2 sepsis patients, alleviates systemic inflammation, and attenuates mortality in a septic mouse model. Altogether, the findings suggest that these nanoparticles have potential applications in the treatment of SARS‐CoV‐2‐related illnesses and other beta‐CoV‐related diseases.