Atherosclerosis is a complex disease affecting arterial blood vessels and blood flow that could result in a variety of life-threatening consequences. Disease models with diverged genomes are necessary for understanding the genetic architecture of this complex disease. Non-obese diabetic (NOD) mice are highly polymorphic and widely used for studies of type 1 diabetes and autoimmunity. Understanding atherosclerosis development in the NOD strain is of particular interest as human atherosclerosis on the diabetic and autoimmune background has not been successfully modeled. In this study, we used CRISPR/Cas9 genome editing to genetically disrupt apolipoprotein E (ApoE) and low-density lipoprotein receptor (LDLR) expression on the pure NOD background, and compared phenotype between single-gene-deleted mice and double-knockout mutants with reference to ApoE-deficient C57BL/6 mice. We found that genetic ablation of Ldlr or Apoe in NOD mice was not sufficient to establish an atherosclerosis model, in contrast to ApoE-deficient C57BL/6 mice fed a high-fat diet (HFD) for over 12 weeks. We further obtained NOD mice deficient in both LDLR and ApoE, and assessed the severity of atherosclerosis and immune response to hyperlipidemia in comparison to ApoE-deficient C57BL/6 mice. Strikingly, the double-knockout NOD mice treated with a HFD developed severe atherosclerosis with aorta narrowed by over 60% by plaques, accompanied by destruction of pancreatic islets and an inflammatory response to hyperlipidemia. Therefore, we succeeded in obtaining a genetic model with severe atherosclerosis on the NOD background, which is highly resistant to the disease. This model is useful for the study of atherosclerosis in the setting of autoimmunity.

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Traditional Chinese medicine (TCM) has been employed as complementary medication against COVID‐19 in China since 2020. Two years since then, TCM, with Lianhua Qingwen (LHQW) as an example, has been included in every version of official clinical protocol guidelines. Recently, LHQW is even distributed to general public at risk but not yet infected. Such common application and widely claimed positive outcome among mild to moderate patients were accompanied by a number of published studies on antiviral, antiinflammatory, and immune modulatory potential using either in vitro or animal models. However, aside from retrospective understanding and open‐labeled clinical trials with relatively small subject size, major gap in conclusive proof for efficacy and safety remains due to the lack of double‐blind placebo‐controlled studies and comprehensive pharmacodynamic and kinetic investigations. This is also supported by a recent WHO expert meeting on this subject, which acknowledged the potential benefits of TCM in mild–moderate cases, while recommended more rigorous studies to further understand effect size, application implications, and outcome determinants. Therefore, there is an urgent need to address the exact role TCM like LHQW could play in COVID‐19 management from translational evidence‐based perspective. High‐quality clinical trials, pharmacological studies, and real‐world data from recent outbreak are recommended.

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