Fig 2: BAT-derived Nrg4 deficiency accelerated endothelium injury and atherosclerosis.Mice aged 6 weeks were fed a WD for 12 weeks (6 mice in each group). a, The vasodilatation reaction induced by Ach (n = 6). b, Representative images of TUNEL staining in sections of thoracic aortas (n = 6). Arrows indicate CD31/TUNEL colocalization. Scale bars, 100 µm. c, The percentage of apoptotic endothelial cells (n = 6). d, Representative electron microscopy images of endothelium. Scale bars, 5 µm. e, Representative images of en face atherosclerotic lesions. f, Quantitative analysis of e (n = 6). g, Representative images of the cross-sectional area of the aortic root (n = 6). Scale bars, 200 µm. h, Quantitative analysis of g. i, Representative immunohistochemical staining images of VSMCs (a-SMA), collagen (Masson), macrophages (anti-CD68) and T lymphocytes (anti-CD3) in aortic plaques. Scale bar, 20 µm. j, Quantitative analysis of I (n = 6). k, Representative H&E staining images of plaque. Dashed lines indicate the contour of the lipid core. Scale bars, 50 µm. l, The quantitative analysis of necrotic core and fibrous cap thickness. The necrotic core was presented as a percentage of lesion area and the fibrous cap thickness was measured at the midpoint and shoulder regions of each lesion and quantified as the ratio of cap thickness to lesion size (n = 6). m, The expressions of MMP2 and MMP9 in mice aortic tissue. n, Quantitative analysis of m (n = 6). Statistical significance was calculated using two-sided Student’s t-tests. The data are presented as the mean ± s.e.m. *P < 0.05; #P < 0.01.Source data

Fig 3: BAT transplantation (BATT) from WT donor alleviated endothelial injury, inflammation and atherosclerosis, and improved metabolic profiles in mice.(A) Representative images of TUNEL staining in sections of thoracic aortas. TUNEL (apoptotic cells, red), anti-CD31 (endothelial cells, green), DAPI (nuclei, blue). Arrows indicate CD31/TUNEL colocalization. Scale bars, 10µm. (B) The percentage of apoptotic endothelial cells (n = 6). (C) The aortic vasodilatation induced by Ach in mice aged 24 weeks (n = 6). (D) Representative electron microscopy images of endothelium in mice. Scale bars, 5µm (n = 6). (E) The mRNA levels of adhesion molecules (VCAM-1, ICAM-1 and E-selectin) and inflammation (TNF-a, IL-1ß and IL-6) in MAECs of mice aged 24 weeks (n = 6). (F) Body weight (n = 6) after BATT weekly (n = 6). (G) The lipid profiles of mice aged 24 weeks among different groups (n = 6). (H) Representative images of en face atherosclerotic lesion areas in AKO and DKO mice. (I) Representative images of the cross-sectional area of the aortic root in AKO and DKO mice. Scale bars, 200µm. (J) Quantitative analysis of (H) (n = 6). (K) Quantitative analysis of (I) (n = 6). (L) Representative immunohistochemical staining images of VSMCs [a–smooth muscle actin (a-SMA)], collagen (Masson), macrophages (anti-CD68), and T lymphocytes (anti-CD3) in aortic plaques. Scale bar, 20 µm. (M) Quantitative analysis of (L) (n = 6). (N) Representative H&E staining images of plaque. A necrotic lipid core is indicated by *; dashed lines indicate the contour of the lipid core; scale bars: 50 µm. (O) The quantitative analysis of necrotic core and fibrous cap thickness. The necrotic core was presented as a percentage of lesion area and the fibrous cap thickness was measured at the midpoint and shoulder regions of each lesion and quantified as the ratio of cap thickness to lesion size (n = 6). (P) The expressions of MMP2 and MMP9 in mice aortic tissue. (Q) Quantitative analysis of (P) (n = 6). For b, c, e, f, and g, P values were calculated by one-way ANOVA with Tukey’s multiple-comparison test. For j, k, m, o and q, P values were calculated by two-sided t-test. Data were shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. Source data

Fig 4: Nrg4 deficiency is associated with atherosclerotic plaque formation in AKO mice.AKO and DKO mice aged 6 weeks were fed a WD for 12 weeks (6 mice in each group). a,b, The vasodilatation reaction induced by Ach (a) and SNP (b) (n = 4). c, Representative images of en face atherosclerotic lesions. d, Quantitative analysis of c (n = 6). e, Representative images of the cross-sectional area of the aortic root (n = 6). Scale bars, 200 µm. f, Quantitative analysis of e. g, Representative immunohistochemical staining images of VSMCs (a-smooth muscle actin (a-SMA)), collagen (Masson), macrophages (anti-CD68) and T lymphocytes (anti-CD3) in aortic plaques. Scale bar, 20 µm. h, Quantitative analysis of g (n = 6). I, Representative hematoxylin and eosin (H&E) staining images of plaque. Dashed lines indicate the contour of necrotic lipid core; scale bars, 50 µm. j, The quantitative analysis of necrotic core and fibrous cap thickness. The necrotic core is presented as a percentage of lesion area and the fibrous cap thickness is measured at the midpoint and shoulder regions of each lesion and quantified as the ratio of cap thickness to lesion size (n = 6). AU, arbitrary units. k, The expressions of matrix metalloproteinase (MMP) 2 and MMP9 in mice aortic tissue. l, Quantitative analysis of k (n = 6). m, The mRNA levels of adhesion molecules (VCAM-1, ICAM-1 and E-selectin) and inflammation (TNF-a, IL-1ß and IL-6) in MAECs of mice (n = 6). Statistical significance was calculated using two-sided Student’s t-tests. The data are presented as mean ± s.e.m. *P < 0.05; #P < 0.01.Source data

Fig 5: In vivo immune-stimulation induced by nanoinhibitor. A Representative photographs of abdominal cavity and mesenteries of mice after different treatments. H&E staining and CD3 immunostained images of tumors in different groups. B Schematic illustration of modified PCI score derived from human PCI score. C IFN-?, TNF-a, and IL-6 concentrations in ascites compared with control group post-treatment. D Modified PCI score of mice individually in different groups. E IFN-?, TNF-a, and IL-6 concentrations in serum compared with control group post-treatment. F Illustration of proposed antitumor mechanism of the nanoinhibitor. ****p < 0.0001