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

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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.

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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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Author notes

  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

Authors
  1. Zhongshan He
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  2. Wei Chen
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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. 19, 1386–1398 (2024). https://doi.org/10.1038/s41565-024-01687-1

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