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Engineering a macromolecular JAK inhibitor for treating acute inflammation and endotoxaemia

Nature Biomedical Engineering (2025)Cite this article

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Abstract

Uncontrolled and sustained inflammation is inextricably associated with the pathogenesis of numerous diseases. However, there is still demand for effective and safe anti-inflammatory therapies. Here we report a potent anti-inflammatory macromolecular therapy named HPL, created by conjugating polyethylene glycol and luminol onto a multivalent and hydrolysable cyclic structure. Leveraging its amphiphilic nature, HPL can spontaneously self-assemble into micelles capable of targeting inflamed tissues and localizing in inflammatory cells. In mice with acute lung, kidney and liver injuries, as well as endotoxaemia, HPL shows anti-inflammatory effects that rivals or surpasses those of two commonly used anti-inflammatory drugs. HPL micelles can act as bioactive and inflammation-responsive carriers for site-specific delivery to release anti-inflammatory drugs. Mechanistically, HPL exerts its anti-inflammatory activity mainly by inhibiting the IL-6/JAK2/STAT3 signalling pathway. HPL shows favourable safety profiles in mice at doses at least 5-fold higher than those used in therapeutic studies. These findings suggest that HPL holds great promise as a highly potent, cost-effective and safe JAK2 inhibitor for treating various diseases associated with inflammation.

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Fig. 1: Schematic illustration of an anti-inflammatory macromolecule and the derived micellar therapy for the treatment of acute inflammatory diseases by normalizing the pathological microenvironment via regulating the JAK2/STAT3 signalling pathway.
Fig. 2: In vitro anti-inflammatory effects of HPL in macrophages and neutrophils.
Fig. 3: In vivo targeting and therapeutic effects of HPL in mice with ALI.
Fig. 4: Therapeutic effects of HPL in AKI mice.
Fig. 5: In vivo targeting and therapeutic effects of HPL in ALF mice.
Fig. 6: In vivo therapeutic effects of HPL in mice with LPS-induced endotoxaemia.
Fig. 7: Therapeutic effects of Rap/HPL in ALI mice.
Fig. 8: HPL reverses inflammatory response by inhibiting the IL-6/JAK2/STAT3 signalling pathway.

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Data availability

The data presented in the study have been provided in the Article and Supplementary Information. The RNA-seq data from mouse lung tissues generated in this study have been deposited in the China National Center for Bioinformation Genome Sequence Archive database under accession number CRA028017 (ref. 75). Source data are provided with this paper.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (number 32271451) to J.Z., the Key Program for Technological Innovation and Application Development of Chongqing (number CSTB2022TIAD-KPX0156) to J.Z., the Key Medical Program Integrated by Chongqing Science and Technology Bureau and Chongqing Health Commission (number 2023GGXM005) to J.Z. and the Graduate Supervisor Team Program of Chongqing in 2022 to J.Z.

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  1. These authors contributed equally: Min Zhou, Yan Wang.

Authors and Affiliations

  1. Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing, China

    Min Zhou, Yan Wang, Bin Yang, Yang Zhang, Ling Zhong, Kaiyao Hu, Wendan Pu & Jianxiang Zhang

  2. Yu-Yue Pathology Scientific Research Center, Chongqing, China

    Min Zhou & Jianxiang Zhang

  3. Department of Pharmacy, The Second Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, China

    Min Zhou

  4. Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China

    Gaoxing Luo & Jianxiang Zhang

  5. State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), Chongqing, China

    Gaoxing Luo & Jianxiang Zhang

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Contributions

J.Z. conceived the project. M.Z., G.L. and J.Z. designed the experiments. M.Z., Y.W., B.Y., Y.Z., L.Z. and K.H. performed all the experiments. M.Z., Y.W., W.P., G.L. and J.Z. analysed the data and composed the manuscript. All authors discussed the results and reviewed the manuscript.

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Correspondence to Gaoxing Luo or Jianxiang Zhang.

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Competing interests

M.Z., K.H. and J.Z. are inventors in a pending patent filed by the China National Intellectual Property Administration (number 2025101169778, 24 January 2025) related to HPL-based therapies, but the rights belong to the Third Military Medical University and Yu-Yue Pathology Scientific Research Center. All other authors declare no competing interests.

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Extended data

Extended Data Fig. 1 Synthesis and characterization of HPL.

a, The synthetic route of HPL. b-d, 1H NMR (b), and FT-IR (c), and UV-visible spectra (d) of different materials. e-f, Matrix-assisted laser desorption/ionization time-of-flight mass spectra of PEG-NH2 (e) and HPL (f).

Source data

Extended Data Fig. 2 Effects of different treatments on cellular uptake of HPL in macrophages.

a, Confocal images showing cellular uptake of HPL in macrophages incubated under various conditions. b-c, Typical flow cytometric profiles (b) and quantitative analysis (c) indicating cellular uptake of Cy5-HPL after different treatments (n = 4 samples). Cells in the control group were incubated with Cy5-HPL in medium alone. In other groups, cells were pre-incubated at 4 °C or pre-treated with different endocytosis inhibitors (including MeβCD, EIPA, cytochalasin D, genistein, and nocodazole) for 1 h, followed by incubation with Cy5-HPL for 2 h. d. Confocal microscopic images show colocalization of Cy5-HPL with endolysosomes. Lysosomes were stained with LysoTracker (green), while nuclei were stained with Hoechst 33342 (blue). The results represent biological replicates, with data expressed as mean ± standard error of the mean. P values were determined using one-way ANOVA followed by the LSD test for multiple comparisons.

Source data

Extended Data Fig. 3 Flow cytometric quantification of Cy5-HPL distribution in neutrophils and macrophages of lung tissues from ALI mice.

a, Typical flow cytometric dot plots show Cy5-HPL distribution profiles in neutrophils and macrophages in lung tissues. b-e, The quantified Cy5+ cell percentages (b, d) and counts (c, e) of neutrophils and macrophages (n = 6 mice). The results represent biological replicates, with data expressed as mean ± standard error of the mean. P values were determined using one-way ANOVA followed by the LSD test for multiple comparisons.

Source data

Extended Data Fig. 4 Analysis of cellular localization of Cy5-HPL in liver tissues of ALF mice.

a-b, Immunofluorescence analysis of the co-localization of Cy5-HPL with Ly6G+ neutrophils (a) and CD68+ macrophages (b) in liver tissue sections. c-d, Flow cytometric quantification of Cy5-HPL+ neutrophils (c) and Cy5-HPL+ macrophages (d) in liver tissues from AFL mice at 24 h after i.v. injection (n = 5 mice). Healthy mice without treatment with Cy5-HPL served as the control. The results represent biological replicates, with data expressed as mean ± standard error of the mean. P values were determined using one-way ANOVA followed by the LSD test for multiple comparisons.

Source data

Extended Data Fig. 5 Comparison of anti-inflammatory effects of HPL and luminol in macrophages.

a-d, The expression levels of TNF-α (a), IL-1β (b), IL-6 (c), and IL-8 (d) in macrophages stimulated with 500 ng/mL of LPS and treated with HPL and luminol sodium salt at the same dose of luminol (16 μmol/L) for 24 h (n = 3 samples). The results represent biological replicates, with data expressed as mean ± standard error of the mean. P values were determined using one-way ANOVA followed by the LSD test for multiple comparisons.

Source data

Extended Data Fig. 6 Comparison of in vivo therapeutic effects of HPL and luminol in ALI mice.

a, The lung wet-to-dry weight ratios of mice after treatment with luminol sodium salt and HPL by i.v. injection at 2.9 mg/kg luminol (n = 5 mice). b-f, The mRNA levels of TNF-α (b), IL-1β (c), IL-6 (d), MPO (e), and IL-8 (f) in lung tissues from ALI mice (n = 5 mice). g-k, The protein levels of TNF-α (g), IL-1β (h), IL-6 (i), IL-8 (j), and MPO (k) in BALFs (n = 5 mice). l-m, Flow cytometric profiles (l) and quantitative analysis (m) of neutrophils in BALFs (n = 5 mice). n, Micrographs of H&E-stained lung tissue sections. The results represent biological replicates, with data expressed as mean ± standard error of the mean. P values were determined using one-way ANOVA followed by the LSD test for multiple comparisons.

Source data

Extended Data Fig. 7 Comparison of in vivo therapeutic effects of HPL and typical anti-inflammatory drugs in ALI mice.

a, Schematic illustration of treatment regimens. b, The lung wet-to-dry weight ratios of mice after treatment with different formulations (n = 5 mice). c-f, The relative mRNA levels of TNF-α (c), IL-1β (d), IL-6 (e), and IL-8 (f) in lung tissues from ALI mice after treatment with different formulations (n = 6 mice). g-j, Quantified relative mRNA levels of TNF-α (g), IL-1β (h), IL-6 (i), and IL-8 (j) in BALFs (n = 3 mice). k, The mRNA level of MPO in lung tissues (n = 6 mice). l-m, Flow cytometric profiles (l) and quantitative analysis (m) of neutrophils in BALFs of ALI mice (n = 5 mice). n, Micrographs of H&E-stained lung tissue sections. Injured lesions in the lung tissues are indicated by black arrows. The results represent biological replicates, with data expressed as mean ± standard error of the mean. P values were determined using one-way ANOVA followed by the LSD test for multiple comparisons.

Source data

Extended Data Fig. 8 RNA-seq analysis of lung tissues from different groups.

a, The volcano map of genes detected in the model versus control groups. b, The volcano map of genes detected in the HPL versus model groups. c, The Veen diagram of DEGs between up-regulated DEGs of the model versus control groups and down-regulated DEGs of the HPL versus model groups. d, Ten significantly enriched biological processes (BP) terms of DEGs between the model and control groups. e, The PPI network of DEGs between the up-regulated DEGs of the model versus control groups and the down-regulated DEGs of the HPL versus model groups. f-g, The MCODE algorithm in Cytoscape to predict the key factors responsible for therapeutic mechanisms of HPL. Control, healthy mice treated with saline. Model, ALI mice induced by LPS and treated with saline. HPL, ALI mice treated with HPL. Replicates are biological.

Source data

Extended Data Fig. 9 Comparison of the anti-inflammatory effects of HPL with Fed.

a-d, The expression levels of TNF-α (a), IL-1β (b), IL-6 (c), and IL-8 (d) in macrophages stimulated with 500 ng/mL of LPS and treated with 5 μmol/L Fed or 16 μmol/L HPL for 24 h (n = 3 samples). The results represent biological replicates, with data expressed as mean ± standard error of the mean. P values were determined using one-way ANOVA followed by the LSD test for multiple comparisons.

Source data

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Supplementary Figs. 1–21, Tables 1 and 2, materials and methods.

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Zhou, M., Wang, Y., Yang, B. et al. Engineering a macromolecular JAK inhibitor for treating acute inflammation and endotoxaemia. Nat. Biomed. Eng (2025). https://doi.org/10.1038/s41551-025-01521-6

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  • DOI: https://doi.org/10.1038/s41551-025-01521-6

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