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Resolvin D1 delivery to lesional macrophages using antioxidative black phosphorus nanosheets for atherosclerosis treatment

Nature Nanotechnology (2024)Cite this article

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Abstract

The buildup of plaques in atherosclerosis leads to cardiovascular events, with chronic unresolved inflammation and overproduction of reactive oxygen species (ROS) being major drivers of plaque progression. Nanotherapeutics that can resolve inflammation and scavenge ROS have the potential to treat atherosclerosis. Here we demonstrate the potential of black phosphorus nanosheets (BPNSs) as a therapeutic agent for the treatment of atherosclerosis. BPNSs can effectively scavenge a broad spectrum of ROS and suppress atherosclerosis-associated pro-inflammatory cytokine production in lesional macrophages. We also demonstrate ROS-responsive, targeted-peptide-modified BPNS-based carriers for the delivery of resolvin D1 (an inflammation-resolving lipid mediator) to lesional macrophages, which further boosts the anti-atherosclerotic efficacy. The targeted nanotherapeutics not only reduce plaque areas but also substantially improve plaque stability in high-fat-diet-fed apolipoprotein E-deficient mice. This study presents a therapeutic strategy against atherosclerosis, and highlights the potential of BPNS-based therapeutics to treat other inflammatory diseases.

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Fig. 1: Schematic of the synthesis strategy and anti-atherosclerotic mechanism of BPNSs@PEG-S2P/R.
Fig. 2: Characterization of BPNSs@PEG-S2P/R and RvD1 loading and release studies.
Fig. 3: In vitro analysis of cellular uptake, ROS-scavenging capability, anti-inflammatory efficacy, ox-LDL uptake and foam cell formation after BPNSs@PEG-S2P/R treatment.
Fig. 4: Pharmacokinetics and biodistribution of BPNSs@PEG-S2P/R.
Fig. 5: Assessment of anti-atherosclerotic efficacy of BPNSs@PEG-S2P/R in Apoe−/− mice by quantifying lesion areas and evaluating the features of plaque stability.
Fig. 6: Single-cell transcriptomics reveal genes and key molecular pathways modulated by BPNSs@PEG-S2P/R treatment in lesional macrophages of the aorta.

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Data availability

All data supporting the findings of this study are available within the Article and its Supplementary Information. Other data are available from the corresponding authors upon reasonable request. Source data are provided with this paper.

References

  1. Moore, K. J. & Tabas, I. Macrophages in the pathogenesis of atherosclerosis. Cell 145, 341–355 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Tabas, I. Macrophage death and defective inflammation resolution in atherosclerosis. Nat. Rev. Immunol. 10, 36–46 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Libby, P. The changing landscape of atherosclerosis. Nature 592, 524–533 (2021).

    Article  CAS  PubMed  Google Scholar 

  4. Chen, W. et al. Macrophage-targeted nanomedicine for the diagnosis and treatment of atherosclerosis. Nat. Rev. Cardiol. 19, 228–249 (2022).

    Article  PubMed  Google Scholar 

  5. Bäck, M., Yurdagul, A., Tabas, I., Öörni, K. & Kovanen, P. T. Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat. Rev. Cardiol. 16, 389–406 (2019).

    PubMed  PubMed Central  Google Scholar 

  6. Kasikara, C., Doran, A. C., Cai, B. & Tabas, I. The role of non-resolving inflammation in atherosclerosis. J. Clin. Invest. 128, 2713–2723 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    Article  CAS  PubMed  Google Scholar 

  8. Ridker, P. M. et al. Low-dose methotrexate for the prevention of atherosclerotic events. N. Engl. J. Med. 380, 752–762 (2019).

    Article  CAS  PubMed  Google Scholar 

  9. Tao, W. et al. siRNA nanoparticles targeting CaMKIIγ in lesional macrophages improve atherosclerotic plaque stability in mice. Sci. Transl. Med. 12, eaay1063 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kamaly, N. et al. Targeted interleukin-10 nanotherapeutics developed with a microfluidic chip enhance resolution of inflammation in advanced atherosclerosis. ACS Nano 10, 5280–5292 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fredman, G. et al. Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice. Sci. Transl. Med. 7, 275ra20 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hansson, G. K. & Hermansson, A. The immune system in atherosclerosis. Nat. Immunol. 12, 204–212 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Wang, Y., Wang, G. Z., Rabinovitch, P. S. & Tabas, I. Macrophage mitochondrial oxidative stress promotes atherosclerosis and nuclear factor-κB-mediated inflammation in macrophages. Circ. Res. 114, 421–433 (2014).

    Article  CAS  PubMed  Google Scholar 

  14. Bentzon, J. F., Otsuka, F., Virmani, R. & Falk, E. Mechanisms of plaque formation and rupture. Circ. Res. 114, 1852–1866 (2014).

    Article  CAS  PubMed  Google Scholar 

  15. Libby, P., Lichtman, A. H. & Hansson, G. K. Immune effector mechanisms implicated in atherosclerosis: from mice to humans. Immunity 38, 1092–1104 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Libby, P., Ridker, P. M. & Hansson, G. K. Progress and challenges in translating the biology of atherosclerosis. Nature 473, 317–325 (2011).

    Article  CAS  PubMed  Google Scholar 

  17. Guo, J. et al. Cyclodextrin-derived intrinsically bioactive nanoparticles for treatment of acute and chronic inflammatory diseases. Adv. Mater. 31, 1904607 (2019).

    Article  CAS  Google Scholar 

  18. Ouyang, J. et al. In situ sprayed NIR-responsive, analgesic black phosphorus-based gel for diabetic ulcer treatment. Proc. Natl Acad. Sci. USA 117, 28667–28677 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hu, K. et al. Marriage of black phosphorus and Cu2+ as effective photothermal agents for PET-guided combination cancer therapy. Nat. Commun. 11, 2778 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Liu, C. et al. Pnictogens in medicinal chemistry: evolution from erstwhile drugs to emerging layered photonic nanomedicine. Chem. Soc. Rev. 50, 2260–2279 (2021).

    Article  CAS  PubMed  Google Scholar 

  21. Tao, W. et al. Emerging two-dimensional monoelemental materials (Xenes) for biomedical applications. Chem. Soc. Rev. 48, 2891–2912 (2019).

    Article  CAS  PubMed  Google Scholar 

  22. Tao, W. et al. Black phosphorus nanosheets as a robust delivery platform for cancer theranostics. Adv. Mater. 29, 1603276 (2017).

    Article  Google Scholar 

  23. Hou, J. et al. Treating acute kidney injury with antioxidative black phosphorus nanosheets. Nano Lett. 20, 1447–1454 (2020).

    Article  CAS  PubMed  Google Scholar 

  24. Fredman, G. et al. An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat. Commun. 7, 12859 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Fredman, G. et al. Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B4 synthesis by inhibiting a calcium-activated kinase pathway. Proc. Natl Acad. Sci. USA 111, 14530–14535 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Huang, X. et al. Synthesis of siRNA nanoparticles to silence plaque-destabilizing gene in atherosclerotic lesional macrophages. Nat. Protoc. 17, 748–780 (2021).

    Article  Google Scholar 

  27. Gao, C. et al. Treatment of atherosclerosis by macrophage-biomimetic nanoparticles via targeted pharmacotherapy and sequestration of proinflammatory cytokines. Nat. Commun. 11, 2622 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cheng, J. et al. A targeting nanotherapy for abdominal aortic aneurysms. J. Am. Coll. Cardiol. 72, 2591–2605 (2018).

    Article  CAS  PubMed  Google Scholar 

  29. Dou, Y. et al. Non-proinflammatory and responsive nanoplatforms for targeted treatment of atherosclerosis. Biomaterials 143, 93–108 (2017).

    Article  CAS  PubMed  Google Scholar 

  30. Lee-Rueckert, M. et al. Acidic extracellular pH promotes accumulation of free cholesterol in human monocyte-derived macrophages via inhibition of ACAT1 activity. Atherosclerosis 312, 1–7 (2020).

    Article  CAS  PubMed  Google Scholar 

  31. Naghavi, M. et al. pH heterogeneity of human and rabbit atherosclerotic plaques; a new insight into detection of vulnerable plaque. Atherosclerosis 164, 27–35 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Liang, X. et al. Highly sensitive H2O2-scavenging nano-bionic system for precise treatment of atherosclerosis. Acta Pharm. Sin. B 13, 372–389 (2023).

    Article  CAS  PubMed  Google Scholar 

  33. Hambleton, J., Weinstein, S. L., Lem, L. & Defranco, A. L. Activation of c-Jun N-terminal kinase in bacterial lipopolysaccharide-stimulated macrophages. Proc. Natl Acad. Sci. USA 93, 2774–2778 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chen, W. et al. Stanene-based nanosheets for β-elemene delivery and ultrasound-mediated combination cancer therapy. Angew. Chem. Int. Ed. 60, 7155–7164 (2021).

    Article  Google Scholar 

  35. Ji, X. et al. Synthesis of ultrathin biotite nanosheets as an intelligent theranostic platform for combination cancer therapy. Adv. Sci. 6, 1901211 (2019).

    Article  CAS  Google Scholar 

  36. Gerlach, B. D. et al. Resolvin D1 promotes the targeting and clearance of necroptotic cells. Cell Death Differ. 27, 525–539 (2020).

    Article  CAS  PubMed  Google Scholar 

  37. Hosseini, Z. et al. Resolvin D1 enhances necroptotic cell clearance through promoting macrophage fatty acid oxidation and oxidative phosphorylation. Arterioscler. Thromb. Vasc. Biol. 41, 1062–1075 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kamaly, N. et al. Development and in vivo efficacy of targeted polymeric inflammation-resolving nanoparticles. Proc. Natl Acad. Sci. USA 110, 6506–6511 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Jo, E. K., Kim, J. K., Shin, D. M. & Sasakawa, C. Molecular mechanisms regulating NLRP3 inflammasome activation. Cell. Mol. Immunol. 13, 148–159 (2016).

    Article  CAS  PubMed  Google Scholar 

  40. Rathinam, V. A. K. & Fitzgerald, K. A. Inflammasome complexes: emerging mechanisms and effector functions. Cell 165, 792–800 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wu, G. et al. Molecularly engineered macrophage‐derived exosomes with inflammation tropism and intrinsic heme biosynthesis for atherosclerosis treatment. Angew. Chem. Int. Ed. 132, 4068–4074 (2020).

    Article  Google Scholar 

  42. Lobatto, M. E., Fuster, V., Fayad, Z. A. & Mulder, W. J. M. Perspectives and opportunities for nanomedicine in the management of atherosclerosis. Nat. Rev. Drug Discov. 10, 835–852 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Duivenvoorden, R. et al. Nanoimmunotherapy to treat ischaemic heart disease. Nat. Rev. Cardiol. 16, 21–32 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Flores, A. M. et al. Nanoparticle therapy for vascular diseases. Arterioscler. Thromb. Vasc. Biol. 39, 635–646 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mulder, W. J. M., Jaffer, F. A., Fayad, Z. A. & Nahrendorf, M. Imaging and nanomedicine in inflammatory atherosclerosis. Sci. Transl. Med. 6, 239sr1 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Lameijer, M. et al. Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates. Nat. Biomed. Eng. 2, 279–292 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Flores, A. M. et al. Pro-efferocytic nanoparticles are specifically taken up by lesional macrophages and prevent atherosclerosis. Nat. Nanotechnol. 15, 154–161 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Fredrikson, G. N. et al. Inhibition of atherosclerosis in apoE-null mice by immunization with apoB-100 peptide sequences. Arterioscler. Thromb. Vasc. Biol. 23, 879–884 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Gough, P. J., Gomez, I. G., Wille, P. T. & Raines, E. W. Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice. J. Clin. Invest. 116, 59–69 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Kong, Y. Z. et al. Macrophage migration inhibitory factor induces MMP-9 expression: implications for destabilization of human atherosclerotic plaques. Atherosclerosis 178, 207–215 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Tang, J. et al. Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation. Sci. Adv. 1, e1400223 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Duivenvoorden, R. et al. A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation. Nat. Commun. 5, 3065 (2014).

    Article  PubMed  Google Scholar 

  53. Nakashiro, S. et al. Pioglitazone-incorporated nanoparticles prevent plaque destabilization and rupture by regulating monocyte/macrophage differentiation in ApoE−/− mice. Arterioscler. Thromb. Vasc. Biol. 36, 491–500 (2016).

    Article  CAS  PubMed  Google Scholar 

  54. Katsuki, S. et al. Nanoparticle-mediated delivery of pitavastatin inhibits atherosclerotic plaque destabilization/rupture in mice by regulating the recruitment of inflammatory monocytes. Circulation 129, 896–906 (2014).

    Article  CAS  PubMed  Google Scholar 

  55. Griendling, K. K. et al. Measurement of reactive oxygen species, reactive nitrogen species, and redox-dependent signaling in the cardiovascular system. Circ. Res. 119, e39–e75 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jung, S. H. et al. Spatiotemporal dynamics of macrophage heterogeneity and a potential function of Trem2hi macrophages in infarcted hearts. Nat. Commun. 13, 4580 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Winkels, H. et al. Atlas of the immune cell repertoire in mouse atherosclerosis defined by single-cell RNA-sequencing and mass cytometry. Circ. Res. 122, 1675–1688 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kim, K. et al. Transcriptome analysis reveals non-foamy rather than foamy plaque macrophages are pro-inflammatory in atherosclerotic murine models. Circ. Res. 123, 1127–1142 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Liu, T. et al. Ultrasmall copper-based nanoparticles for reactive oxygen species scavenging and alleviation of inflammation related diseases. Nat. Commun. 11, 2788 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ni, S. H. et al. Single-cell transcriptomic analyses of cardiac immune cells reveal that Rel-driven CD72-positive macrophages induce cardiomyocyte injury. Cardiovasc. Res. 118, 1303–1320 (2022).

    Article  CAS  PubMed  Google Scholar 

  61. Jin, Z.-H. et al. Radiotheranostic agent 64Cu-cyclam-RAFT-c(-RGDfK-)4 for management of peritoneal metastasis in ovarian cancer. Clin. Cancer Res. 26, 6230–6241 (2020).

  62. Jiang, Y. et al. Wireless, closed-loop, smart bandage with integrated sensors and stimulators for advanced wound care and accelerated healing. Nat. Biotechnol. 41, 652–662 (2023).

    Article  CAS  PubMed  Google Scholar 

  63. Li, Y. et al. Single-cell transcriptome analysis reveals dynamic cell populations and differential gene expression patterns in control and aneurysmal human aortic tissue. Circulation 142, 1374–1388 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Cochain, C. et al. Single-cell RNA-seq reveals the transcriptional landscape and heterogeneity of aortic macrophages in murine atherosclerosis. Circ. Res. 122, 1661–1674 (2018).

    Article  CAS  PubMed  Google Scholar 

  65. McArdle, S. et al. Migratory and dancing macrophage subsets in atherosclerotic lesions. Circ. Res. 125, 1038–1051 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work is supported by the American Heart Association (AHA) Transformational Project Award (23TPA1072337, to W.T.), AHA’s Second Century Early Faculty Independence Award (23SCEFIA1151841, to W.T.), AHA Collaborative Sciences Award (2018A004190, to W.T.), Harvard/Brigham Department of Anesthesiology—Basic Scientist Grant (2420 BPA075, to W.T.), Khoury Innovation Award (2020A003219, to W.T.), Nanotechnology Foundation (2022A002721, to W.T.), and Distinguished Chair Professorship Foundation (018129, to W.T.). This work was also financially supported by the National Key S&T Special Projects (2018ZX09201018-024, to X.S.), National Key R&D Program of China (2023YFC3403200, to X.S.), Sichuan Province Science and Technology Support Program (2020JDRC0052, to X.S.), General Program of Natural Science Foundation of Sichuan Province (2024NSFSC0714, to Z.H.), the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences (2022-RC350-04, to K.H.), the CAMS Innovation Fund for Medical Sciences (nos. 2022-I2M-1-026-1 and 2022-I2M-2-002, to K.H.), Beijing Nova Program (to K.H.) and JSPS KAKENHI grant (no. 21H0287, to K.H.). W.T. also acknowledges the funding supports from the American Lung Association (ALA) Cancer Discovery Award (LCD1034625), ALA Courtney Cox Cole Lung Cancer Research Award (2022A017206), American Society of Transplantation (AST) Career Transition Grant (1173492), Novo Nordisk ValidatioNN Award (2023A009607), Harvard/Brigham Health & Technology Innovation Fund (2023A004452), and Gillian Reny Stepping Strong Center for Trauma Innovation Breakthrough Innovator Award (113548). We acknowledge technical support from the Laboratory of Mitochondria and Metabolism, West China Hospital, Sichuan University.

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  1. These authors contributed equally: Zhongshan He, Wei Chen, Kuan Hu.

Authors and Affiliations

  1. Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China

    Zhongshan He, Yaoyao Luo, Xi He, Tingting Li, Qin Xu, Shuping Yang, Mengran Guo, Wei Zou, Yanfei Li, Lingjing Huang & Xiangrong Song

  2. Center for Nanomedicine and Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Wei Chen, Kuan Hu, Jiang Ouyang, Yongjiang Li, Qimanguli Saiding, Na Kong & Wei Tao

  3. Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, Chiba, Japan

    Kuan Hu, Lin Xie, Yiding Zhang & Ming-Rong Zhang

  4. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Kuan Hu & Rui Wang

  5. Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, China

    Wanqin Zeng & Lu Chen

  6. Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA

    Xingcai Zhang

  7. College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, China

    Tian Xie

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  1. Zhongshan He
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Contributions

Z.H., W.C., K.H., X.S. and W.T. conceived and designed the project. Z.H., X.H., Q.X., S.Y., M.G., W.Z., Y. Li and L.H. synthesized and characterized the materials and performed the in vitro experiments. Z.H., K.H., Y. Luo, W. Zeng, X.H., T.L., L.X., Y.Z., Q.X., S.Y., M.G., W. Zou, Y. Li, L.H. and L.C. performed the in vivo experiments. Z.H., W.C. and K.H. discussed the results and interpreted the data. W.C., X.S. and W.T. supervised the project. Z.H., W.C., K.H., J.O., Y. Li, Q.S., R.W., N.K., X.Z., T.X., M.-R.Z., X.S. and W.T. co-wrote the manuscript, and all authors edited and approved it before submission.

Corresponding authors

Correspondence to Wei Chen, Xiangrong Song or Wei Tao.

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Competing interests

W.T. has received consultancy fees, lecture fees, been on the scientific advisory board, or conducted sponsored research at Harvard Medical School/Brigham and Women’s Hospital for the following entities: Novo Nordisk A/S, Henlius USA Inc. The other authors declare no competing interests.

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Extended data

Extended Data Fig. 1 Inhibition of atherosclerotic plaque destabilization and rupture by BPNSs@PEG-S2P/R in plaque-bearing angiotensin-infused ApoE−/− mice.

a, Schematic illustration of the timeline and treatment protocol for the angiotensin-infused atherosclerotic plaque rupture model. Fourteen-week-old ApoE−/− mice were fed a HFD for 4 weeks and then received 4 weeks of different treatments with angiotensin II infusion while continuing on the HFD. One day after the last administration, samples were collected from the treated mice to assess therapeutic efficacy. b, Representative microscope images of atherosclerotic plaques in brachiocephalic artery sections stained using H&E and Elastica van Gieson (EVG). The black arrows in EVG staining denote the disrupted/buried fibrous caps within the atherosclerotic plaques of brachiocephalic arteries. Scale bars = 100 µm. c, Quantitative analysis of the total necrotic area and the ratio of necrotic area to the total plaque area in sections of brachiocephalic artery using H&E staining (n = 10 biologically independent mice). d, Quantitative analysis of the number of disrupted/buried fibrous caps, and fibrous cap thickness in atherosclerotic plaques of sections from the brachiocephalic artery using EVG staining (n = 10 biologically independent mice). Disrupted/buried fibrous caps are indicated by arrowheads. e, f, Representative microscope images of aortic root sections stained with (e) ORO, and (f) Masson’s trichrome. Scale bars = 200 µm. The ‘red stars’ in (f) of Masson’s trichrome staining denote the necrotic core area within the aortic roots. g-i, Quantitative analysis of the (g) ORO-positive lesion area, (h) total necrotic core area, and (i) collagen area in atherosclerotic plaques of sections from aortic root (n = 10 biologically independent mice). Data were analyzed using one-way ANOVA with a Dunnett T3 post hoc test, and are shown as mean ± S.D of 10 biologically independent mice in all indicated groups. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, and ns denotes no significance. Cartoon mouse was created with BioRender.com.

Source data

Extended Data Fig. 2 Mechanistic analysis of the anti-atherosclerotic effects of BPNSs@PEG-S2P/R in vivo.

a, Representative fluorescence microscope images of DHE-stained sections of the aortic root from ApoE−/− mice subjected to different treatments. Scale bars = 200 µm. b, Quantitative analysis of the ratio of DHE fluorescence to the plaque area in aortic root sections (n = 10 biologically independent mice). c, d, Serum levels of H2O2 and ox-LDL in plaque-bearing ApoE−/− mice after receiving different treatments (n = 10 biologically independent mice). Wild-type C57BL/6J mice served as a comparison group. e, Immunofluorescence staining and (f) quantitative analysis of NF-κB, IL-6, and IL-10 in aortic root sections from mice treated with different formulations (n = 10 biologically independent mice). Cell nuclei were stained with DAPI. Scale bars = 50 µm. g, Serum levels of TNF-α, IL-1β, and IL-6 in plaque-bearing ApoE−/− mice after receiving different treatments (n = 10 biologically independent mice). Wild-type C57BL/6J mice served as a comparison group. Data were analyzed using one-way ANOVA with a Dunnett T3 post hoc test, and shown as mean ± S.D. *p < 0.05, **p < 0.01, ***p < 0.001 and ****p < 0.0001, and ns denotes no significance.

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Supplementary Figs. 1–53, Tables 1–3, Results, discussion and references.

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Source Data Fig. 1-5 and Source Data Extended Data Fig. 1,2

Statistical data.

Source Data Fig. 6

Single-cell sequencing data for Fig. 6

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He, Z., Chen, W., Hu, K. et al. Resolvin D1 delivery to lesional macrophages using antioxidative black phosphorus nanosheets for atherosclerosis treatment. Nat. Nanotechnol. (2024). https://doi.org/10.1038/s41565-024-01687-1

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