Annexin A1 mRNA-loaded liposomes alleviate acute pancreatitis by suppressing STING pathway and promoting efferocytosis in macrophages

Posted on
annexin-a1-mrna-loaded-liposomes-alleviate-acute-pancreatitis-by-suppressing-sting-pathway-and-promoting-efferocytosis-in-macrophages
Annexin A1 mRNA-loaded liposomes alleviate acute pancreatitis by suppressing STING pathway and promoting efferocytosis in macrophages

Data availability

Data supporting the findings of this study are available in the article and its Supplementary Information. Bulk RNA-seq data have been deposited in Gene Expression Omnibus under accession no. GSE249714. The proteomics data have been deposited in iProX database consortium under accession no. IPX0007564002. Source data are provided with this paper.

References

  1. Mederos, M. A., Reber, H. A. & Girgis, M. D. Acute pancreatitis: a review. JAMA 325, 382–390 (2021).

    CAS  PubMed  Google Scholar 

  2. Jaber, S. et al. Guidelines for the management of patients with severe acute pancreatitis, 2021. Anaesth. Crit. Care Pain. Med 41, 101060 (2022).

    PubMed  Google Scholar 

  3. Banks, P. A. et al. Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by international consensus. Gut 62, 102–111 (2013).

    PubMed  Google Scholar 

  4. Mareninova, O. A. et al. Cell death in pancreatitis: caspases protect from necrotizing pancreatitis. J. Biol. Chem. 281, 3370–3381 (2006).

    CAS  PubMed  Google Scholar 

  5. Louhimo, J., Steer, M. L. & Perides, G. Necroptosis is an important severity determinant and potential therapeutic target in experimental severe pancreatitis. Cell Mol. Gastroenterol. Hepatol. 2, 519–535 (2016).

    PubMed  PubMed Central  Google Scholar 

  6. Cao, Y., Adhikari, S., Clément, M. V., Wallig, M. & Bhatia, M. Induction of apoptosis by crambene protects mice against acute pancreatitis via anti-inflammatory pathways. Am. J. Pathol. 170, 1521–1534 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhu, Q. et al. The TRIM28/miR133a/CD47 axis acts as a potential therapeutic target in pancreatic necrosis by impairing efferocytosis. Mol. Ther. 32, 3025–3041 (2024).

    CAS  PubMed  Google Scholar 

  8. Tashiro, M., Schäfer, C., Yao, H., Ernst, S. A. & Williams, J. A. Arginine induced acute pancreatitis alters the actin cytoskeleton and increases heat shock protein expression in rat pancreatic acinar cells. Gut 49, 241–250 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Hoque, R., Malik, A. F., Gorelick, F. & Mehal, W. Z. Sterile inflammatory response in acute pancreatitis. Pancreas 41, 353–357 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhao, Q., Wei, Y., Pandol, S. J., Li, L. & Habtezion, A. STING signaling promotes inflammation in experimental acute pancreatitis. Gastroenterology 154, 1822–1835.e2 (2018).

  11. Sendler, M. et al. NLRP3 inflammasome regulates development of systemic inflammatory response and compensatory anti-inflammatory response syndromes in mice with acute pancreatitis. Gastroenterology 158, 253–269.e14 (2020).

  12. Nagata, S. Apoptosis and clearance of apoptotic cells. Annu Rev. Immunol. 36, 489–517 (2018).

    CAS  PubMed  Google Scholar 

  13. Arandjelovic, S. & Ravichandran, K. S. Phagocytosis of apoptotic cells in homeostasis. Nat. Immunol. 16, 907–917 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Vago, J. P. et al. Proresolving actions of synthetic and natural protease inhibitors are mediated by annexin A1. J. Immunol. 196, 1922–1932 (2016).

    CAS  PubMed  Google Scholar 

  15. Shen, X., Zhang, S., Guo, Z., Xing, D. & Chen, W. The crosstalk of ABCA1 and ANXA1: a potential mechanism for protection against atherosclerosis. Mol. Med 26, 84 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. McArthur, S. et al. Annexin A1: a central player in the anti-inflammatory and neuroprotective role of microglia. J. Immunol. 185, 6317–6328 (2010).

    CAS  PubMed  Google Scholar 

  17. Tzelepis, F. et al. Annexin1 regulates DC efferocytosis and cross-presentation during Mycobacterium tuberculosis infection. J. Clin. Invest. 125, 752–768 (2015).

    PubMed  Google Scholar 

  18. da Rocha, G. H. O. et al. Control of expression and activity of peroxisome proliferated-activated receptor γ by annexin A1 on microglia during efferocytosis. Cell Biochem. Funct. 37, 560–568 (2019).

    PubMed  Google Scholar 

  19. Sun, L., Wu, J., Du, F., Chen, X. & Chen, Z. J. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339, 786–791 (2013).

    CAS  PubMed  Google Scholar 

  20. Gao, D. et al. Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses. Science 341, 903–906 (2013).

    CAS  PubMed  Google Scholar 

  21. Wu, J. et al. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339, 826–830 (2013).

    CAS  PubMed  Google Scholar 

  22. Wang, Z. et al. Development and applications of mRNA treatment based on lipid nanoparticles. Biotechnol. Adv. 65, 108130 (2023).

    CAS  PubMed  Google Scholar 

  23. Patel, S. K. et al. Hydroxycholesterol substitution in ionizable lipid nanoparticles for mRNA delivery to T cells. J. Control. Release 347, 521–532 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Bitounis, D., Jacquinet, E., Rogers, M. A. & Amiji, M. M. Strategies to reduce the risks of mRNA drug and vaccine toxicity. Nat. Rev. Drug Discov. 23, 281–300 (2024).

    CAS  PubMed  Google Scholar 

  25. Kon, E., Ad-El, N., Hazan-Halevy, I., Stotsky-Oterin, L. & Peer, D. Targeting cancer with mRNA-lipid nanoparticles: key considerations and future prospects. Nat. Rev. Clin. Oncol. 20, 739–754 (2023).

    CAS  PubMed  Google Scholar 

  26. Kumari, A., Kaur, A. & Aggarwal, G. The emerging potential of siRNA nanotherapeutics in treatment of arthritis. Asian J. Pharm. Sci. 18, 100845 (2023).

    PubMed  PubMed Central  Google Scholar 

  27. Li, Z. et al. Synergistic dual cell therapy for atherosclerosis regression: ROS-responsive bio-liposomes co-loaded with geniposide and emodin. J. Nanobiotechnol. 22, 129 (2024).

    CAS  Google Scholar 

  28. Nasra, S., Bhatia, D. & Kumar, A. Targeted macrophage re-programming: synergistic therapy with methotrexate and RELA siRNA folate-liposome in RAW264.7 cells and arthritic rats. Adv. Health. Mater. 13, e2400679 (2024).

    Google Scholar 

  29. Ma, J., Ding, L., Peng, X., Jiang, L. & Liu, G. Recent advances of engineered cell membrane-based nanotherapeutics to combat inflammatory diseases. Small 20, e2308646 (2024).

    PubMed  Google Scholar 

  30. Dai, Q. et al. Quantifying the ligand-coated nanoparticle delivery to cancer cells in solid tumors. ACS Nano 12, 8423–8435 (2018).

    CAS  PubMed  Google Scholar 

  31. Yan, H. et al. Engineering cell membrane-based nanotherapeutics to target inflammation. Adv. Sci. 6, 1900605 (2019).

    Google Scholar 

  32. Melendez, E. et al. Natural killer cells act as an extrinsic barrier for in vivo reprogramming. Development 149, dev200361 (2022).

  33. Wu, J. et al. Macrophage phenotypic switch orchestrates the inflammation and repair/regeneration following acute pancreatitis injury. eBioMedicine 58, 102920 (2020).

    PubMed  PubMed Central  Google Scholar 

  34. Manohar, M. et al. Novel circulating and tissue monocytes as well as macrophages in pancreatitis and recovery. Gastroenterology 161, 2014–2029 (2021).

  35. Wu, L. et al. Annexin A1 alleviates kidney injury by promoting the resolution of inflammation in diabetic nephropathy. Kidney Int. 100, 107–121 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu, X. et al. USP25 deficiency exacerbates acute pancreatitis via up-regulating TBK1-NF-κB signaling in macrophages. Cell Mol. Gastroenterol. Hepatol. 14, 1103–1122 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Wan, J. C. M. et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat. Rev. Cancer 17, 223–238 (2017).

    CAS  PubMed  Google Scholar 

  38. Maltbaek, J. H., Cambier, S., Snyder, J. M. & Stetson, D. B. ABCC1 transporter exports the immunostimulatory cyclic dinucleotide cGAMP. Immunity 55, 1799–1812 (2022).

  39. Zhou, Y. et al. Blockade of the phagocytic receptor MerTK on tumor-associated macrophages enhances P2X7R-dependent STING activation by tumor-derived cGAMP. Immunity 52, 357–373.e9 (2020).

  40. Lee, G. Y. et al. Hyaluronic acid nanoparticles for active targeting atherosclerosis. Biomaterials 53, 341–348 (2015).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhou, M. et al. Targeted delivery of hyaluronic acid-coated solid lipid nanoparticles for rheumatoid arthritis therapy. Drug Deliv. 25, 716–722 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Sousa de Almeida, M. et al. Understanding nanoparticle endocytosis to improve targeting strategies in nanomedicine. Chem. Soc. Rev. 50, 5397–5434 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Pan, Y. et al. Synergistic inhibition of pancreatic cancer with anti-PD-L1 and c-Myc inhibitor JQ1. Oncoimmunology 8, e1581529 (2019).

    PubMed  PubMed Central  Google Scholar 

  45. Pan, Y. et al. Development of a novel model of hypertriglyceridemic acute pancreatitis in mice. Sci. Rep. 7, 40799 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Sendler, M. et al. Cathepsin B-mediated activation of trypsinogen in endocytosing macrophages increases severity of pancreatitis in mice. Gastroenterology 154, 704–718.e10 (2018).

  47. Deng, L. et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41, 843–852 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Ahn, J., Xia, T., Rabasa Capote, A., Betancourt, D. & Barber, G. N. Extrinsic phagocyte-dependent STING signaling dictates the immunogenicity of dying cells. Cancer Cell 33, 862–873.e5 (2018).

  49. Ablasser, A. et al. Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature 503, 530–534 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Luteijn, R. D. et al. SLC19A1 transports immunoreactive cyclic dinucleotides. Nature 573, 434–438 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhou, C. et al. Transfer of cGAMP into bystander cells via LRRC8 volume-regulated anion channels augments STING-mediated interferon responses and anti-viral immunity. Immunity 52, 767–781.e6 (2020).

  52. Kosicka, A. et al. Attenuation of plasma annexin A1 in human obesity. FASEB J. 27, 368–378 (2013).

    CAS  PubMed  Google Scholar 

  53. De Ponti, F. F. & Scott, C. L. Modulating hepatic macrophages with annexin A1 in non-alcoholic steatohepatitis. Clin. Sci. 136, 1111–1115 (2022).

    Google Scholar 

  54. Locatelli, I. et al. Endogenous annexin A1 is a novel protective determinant in nonalcoholic steatohepatitis in mice. Hepatology 60, 531–544 (2014).

    CAS  PubMed  Google Scholar 

  55. Morioka, S. et al. Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release. Nature 563, 714–718 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Pan, Y. et al. Single-cell RNA sequencing reveals compartmental remodeling of tumor-infiltrating immune cells induced by anti-CD47 targeting in pancreatic cancer. J. Hematol. Oncol. 12, 124 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Chondronasiou, D. et al. Deciphering the roadmap of in vivo reprogramming toward pluripotency. Stem Cell Rep. 17, 2501–2517 (2022).

    CAS  Google Scholar 

  58. He, R. et al. SULF2 enhances GDF15-SMAD axis to facilitate the initiation and progression of pancreatic cancer. Cancer Lett. 538, 215693 (2022).

    CAS  PubMed  Google Scholar 

  59. Li, L. et al. Integrative proteogenomic characterization of early esophageal cancer. Nat. Commun. 14, 1666 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Hamilton, A. G. et al. Ionizable lipid nanoparticles with integrated immune checkpoint inhibition for mRNA CAR T cell engineering. Adv. Health. Mater. 12, e2301515 (2023).

    Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by the Joint Funds for the innovation of Science and Technology, Fujian province (2024Y9277 to Y.P.), Excellent Young Scholars Cultivation Project of Fujian Medical University Union Hospital (2022XH025 to Y.P.) and National Natural Science Foundation of China (no. 82103310 to Y.P.). J.C. acknowledges the Fundação Ciência e Tecnologia, IP national support, through UID/04923 – Comprehensive Health Research Centre.

Author information

Author notes

  1. These authors contributed equally: Haizong Fang, Peidong You, Shengzhe Lin, Yuwei Wu, Jiajing Lin, Zelin Hou.

Authors and Affiliations

  1. Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China

    Haizong Fang, Peidong You, Yuwei Wu, Jiajing Lin, Zelin Hou, Feihong Liang, Changgan Chen, Zhiyuan Wang, Fengchun Lu, Heguang Huang & Yu Pan

  2. Department of Pathology, Second Hospital of Shandong University, Jinan, People’s Republic of China

    Peidong You

  3. Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China

    Shengzhe Lin

  4. Fujian Medical University Cancer Center, Fuzhou, People’s Republic of China

    Shengzhe Lin & Feihong Liang

  5. Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China

    Yuwei Wu & Yu Pan

  6. Department of Pathology, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China

    Linlin Chen & Shihan Zhang

  7. The Cancer Center, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China

    Xiaolan Chen

  8. School of Nursing, Yunnan University of Chinese Medicine, Kunming, People’s Republic of China

    Kui Zhao

  9. Stanford University School of Medicine, Palo Alto, CA, USA

    Minggui Pan

  10. The Second Department of Oncology, Huizhou First Hospital, Huizhou, People’s Republic of China

    Yundong Zhou

  11. Faculty of Medicine, Macau University of Science and Technology, Macau, People’s Republic of China

    Chengliang Yin

  12. Comprehensive Health Research Centre (CHRC), NOVA Medical School, Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, Lisbon, Portugal

    João Conde

Authors

  1. Haizong Fang
  2. Peidong You
  3. Shengzhe Lin
  4. Yuwei Wu
  5. Jiajing Lin
  6. Zelin Hou
  7. Feihong Liang
  8. Changgan Chen
  9. Zhiyuan Wang
  10. Linlin Chen
  11. Shihan Zhang
  12. Xiaolan Chen
  13. Kui Zhao
  14. Fengchun Lu
  15. Minggui Pan
  16. Yundong Zhou
  17. Chengliang Yin
  18. João Conde
  19. Heguang Huang
  20. Yu Pan

Contributions

H.F.: methodology, data analysis and investigation. P.Y.: software, methodology, data analysis and investigation. S.L.: methodology, data analysis, investigation and writing—original draft. Y.W.: investigation, methodology, data analysis and methodology. J.L.: methodology, investigation, software and data analysis. Z.H.: conceptualization, methodology and investigation. F. Liang: methodology, investigation and data analysis. C.C.: methodology and investigation. Z.W.: methodology and investigation. L.C.: methodology and investigation. S.Z.: methodology and investigation. X.C.: methodology and investigation. K.Z.: methodology and data analysis. F. Lu: methodology and investigation. M.P.: data analysis, methodology, paper editing and revision. Y.Z.: paper editing and revision. C.Y.: conceptualization, methodology, investigation and writing—original draft. J.C.: conceptualization, methodology, investigation and writing—original draft. H.H.: conceptualization, methodology, investigation and writing—original draft. Y.P.: conceptualization, methodology, data analysis, investigation, writing—original draft—and revision. All authors have given approval to the final version of the paper.

Corresponding authors

Correspondence to Chengliang Yin, João Conde, Heguang Huang or Yu Pan.

Ethics declarations

Competing interests

J.C. is a co-founder and shareholder of TargTex S.A. Targeted therapeutics for Glioblastoma Multiforme. J.C. is also a member of the Global Burden Disease (GBD) consortium from Institute for Health Metrics and Evaluation (IHME), University of Washington. Y.P., F. Liang and P.Y. are authors of a provisional patent (202411349874.8, China) based on this paper. The other authors declare no competing interests.

Peer review

Peer review information

Nature Nanotechnology thanks Mansoor Amiji and Matthias Sendler for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Myeloid Anxa1 expression in the mouse pancreas during AP.

(a) RNA-seq of pancreas in AP mice with different time points. (b) Anxa1 mRNA expression in the pancreas in AP mice at different time points. * indicates compared with control; # indicates compared with 24 h; NS, not significant as compared with control. (c) Monocyte abundance of pancreas in AP mice with different time points. * indicates compared with control; (d) Macrophage abundance in the pancreas in AP mice at different time points. * indicates compared with control; NS, not significant as compared with control. (e) Correlation between monocyte/macrophage abundance and the expression of Anxa1. (f) UMAP plot showing 6 immune cell clusters in the pancreas of AP mice. (g) Fraction of 6 immune cell clusters in each sample. (h) Dot plot depicting percent expression and average expression of Anxa1 in CER and control groups. (i) Flow cytometry analysis of Anxa1 expression in CD45+F4/80+ cells from the mouse pancreas during AP and recovery. *P < 0.01 as compared with 0 h; #P < 0.05 as compared with 12 h; NS, not significant as compared with 0 h. (j) Flow cytometry analysis of Anxa1 expression in CD45+F4/80+ and CD45+F4/80− cells from CER mice. NS, not significant as compared with control. Data are presented as means ± SD of n = 3 (b–d), n = 5 (i), or n = 10 (j) biologically independent samples per group. Data are presented as means ± SD of n ≥ 3 (b–d), n = 5 (i), or n = 10 (j) biologically independent samples per group. P values were determined by one-way ANOVA with Dunnett’s post-hoc test (b–d), Spearman’s correlation (e), unpaired two-tailed Student’s t-test (j) or one-way ANOVA with Tukey’s post-hoc test (i). Illustrations in a created with Figdraw.com.

Source data

Extended Data Fig. 2 The type I IFN response induced by Anxa1-deficient mice requires ATP-binding cassette transporter ABCG2.

(a) Scheme for KO-143 treatment of Anxa1CKO AP mice induced with 7 hourly injections of cerulein. (b) Pancreas histology scores of PBS- and KO-143-treated saline-control (Control) or AP mice. (c) Immunoblot analysis of ABCG2, c-Casp3, IFN-β, p-TBK1, TBK1, p-IRF3, IRF3, p-P65, and P65 in pancreas tissues of PBS- and KO-143-treated AP mice. (d) Anxa1CKO Abcg+/+ and Anxa1CKO Abcg2−/− mice were induced with 7 hourly injections of cerulein. (e) Immunoblot analysis of ABCG2, c-Casp3, IFN-β, p-TBK1, TBK1, p-IRF3, IRF3, p-P65, and P65 in pancreas tissues of cerulein-treated (AP) Anxa1CKO Abcg+/+ and Anxa1CKO Abcg2−/− mice. (f) Pancreas histology scores for Anxa1CKO Abcg+/+ and Anxa1CKO Abcg2−/−, saline-treated (NaCl) or AP mice. (g) Schematic sketch. Up: Anxa1 (A1) binds with high affinity to phosphatidylserine (PS) on the surface of apoptotic cells in a calcium (Ca+)-dependent manner, and contributes to the engulfment of apoptotic cells by efferocytosis of macrophages. Down: The deficiency of Anxa1 in macrophages impairs the clearance of apoptotic cells, triggering increased cGAMP production in the apoptotic or necrotic acinar cells which in turn enters the macrophages through ABCG2 transporter and activates STING/TBK1/NFκB signaling to induce the production of type I IFN. Data are presented as means ± SD of n = 5 (b, d) biologically independent samples per group. P values were determined by one-way ANOVA with Tukey’s post-hoc test (B.D). Illustrations in a and d created with Figdraw.com.

Source data

Extended Data Fig. 3 Characterization and targeting capability of HA-M@Lip@Anxa1 NPs.

(a) The mRNA contents per µg for Lip@Anxa1 NPs at the feeding different ration (mRNA:phosphatidylcholine). (b) TEM of HA-M@Lip@Anxa1 NPs. Scale bars = 100 nm. (c) Hydrodynamic size distribution of different NPs. (d) ζ-potential measurement of different NPs. (e) Representative images of CLSM and (f) quantification analysis of RAW 264.7 cells with nuclei staining by Hoechst 33342 incubated with Lip NPs, M@Lip NPs, and HA-M@Lip NPs for 4 h after activation by LPS (+) or not. Inflammatory macrophages were treated with HA solution and HA-M@Lip NPs. Scale bars = 60 μm. (g) The schematic diagram showed that acinar cells were co-cultured with inflammatory macrophages in a transwell system for simulating plaque in vitro. (h) Phagocytosis of HA-M@Lip NPs in acinar cells and inflammatory macrophages in transwell. BF indicates bright field. Scale bars = 60μm. (i) Fluorescence quantitation of HA-M@Lip NPs (red). (j) RAW 264.7 cells without any treatment were used as control. Adding LPS as the model group. Western blot assay of Anxa1 expression in macrophages (LPS+) treatment with Anxa1, M@Lip@Anxa1, HA-M@Lip@Anxa1, and Lip@Anxa1. (K&L) Fluorescence images and quantitative analysis of mice after being treated with different formulations. ***P < 0.001. Data are presented as means ± SD of n = 3 biologically independent samples (a, d, f, i, j, l). P values were determined by unpaired two-tailed Student’s t-test (i) or one-way ANOVA with Tukey’s post-hoc test (f, l).

Source data

Extended Data Fig. 4 Myeloid Anxa1 deficiency exacerbates SAP.

(a) Pancreas histology scores in Anxa1f/f and Anxa1CKO mice that were saline-treated (NaCl group) or L-arginine-treated (SAP group). The proportion of apoptotic (b) and necrotic cells (c) in pancreas tissues. Pancreas IFN-β (d), TNF-α (e), IL-6 (f), and MCP-1 (g) in Anxa1f/f and Anxa1CKO NaCl or SAP mice. (h) (a) Representative immunoblot analysis of TLR4, STING, p-TBK1, TBK1, p-P65, P65, and NLRP3 in pancreas tissues from Anxa1f/f SAP and Anxa1CKO SAP mice. HA-M@Lip@Anxa1 NPs treatment of SAP mice induced with injection of L-arginine. The pancreas pathology score (i), phagocytic index (j), pancreas IFN-β (k), TNF-α (l), IL-6 (m), and MCP-1 (n) in phosphate buffer saline (PBS) and HA-M@Lip@Anxa1 NPs-treated saline control (Con) and SAP mice. (o) Immunoblot analysis of TLR4, STING, p-TBK1, TBK1, p-P65, P65, and NLRP3 in pancreas tissues of SAP mice after receiving PBS or HA-M@Lip@Anxa1 NPs treatment. Data are presented as means ± SD of n = 5 biologically independent samples (a–g, i–n). P values are determined by unpaired two-tailed Student’s t-test (b–g, j–n) or one-way ANOVA with Tukey’s post-hoc test (a and i).

Source data

Supplementary information

Source data

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fang, H., You, P., Lin, S. et al. Annexin A1 mRNA-loaded liposomes alleviate acute pancreatitis by suppressing STING pathway and promoting efferocytosis in macrophages. Nat. Nanotechnol. (2025). https://doi.org/10.1038/s41565-025-01979-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41565-025-01979-0