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Effective combinatorial antifungal therapy using a host defense peptide mimic that self-assembles into delivery micelles

Nature Biotechnology (2026)Cite this article

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Abstract

The synergistic combination of two antimicrobial drugs is a promising therapeutic modality for many infectious diseases. However, systemic fungal infections still have a high mortality rate because of distinct in vivo distributions of the two drugs. Here we address this challenge by designing an antifungal polymer that forms micelles suitable for delivering a second antifungal agent to achieve temporal and spatial consistency of delivery. We show that the polymer, which mimics host defense peptides, exerts a synergistic effect with the antifungal amphotericin B (AmB). The AmB-encapsulated micelles (AmBmicelles) greatly reduce the toxicity of AmB through slow release and expand its therapeutic window in vivo. AmBmicelles can selectively target fungal pathogens through charge interactions with the fungal membrane. In mouse models of systemic candidiasis and cryptococcal meningitis, AmBmicelles increase the survival rate by 67–100% compared to the state-of-the-art drug AmBisome or AmBisome and 5-flucytosine combination, suggesting that the strategy may be effective in combating drug-resistant fungal infections including meningitis.

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Fig. 1: The current clinical strategy and our strategy in treating fungal infections.
Fig. 2: Synthesis, characterization and biological activity study of polymers and polymer micelles.
Fig. 3: Mechanism of synergistic effect between micelles and AmB and fungal pathogen selective targeting ability of micelles.
Fig. 4: The biocompatibility and therapeutic efficacy of AmBmicelles.
Fig. 5: The therapeutic efficacy of AmBmicelles in fungal meningitis.

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All data needed to evaluate the conclusions are available within the article or its Supplementary Information. Any additional data are available from the corresponding author. Source data are provided with this paper.

References

  1. GBD 2021 Antimicrobial Resistance Collaborators Global burden of bacterial antimicrobial resistance 1990–2021: a systematic analysis with forecasts to 2050. Lancet 404, 1199–1226 (2024).

    Article  Google Scholar 

  2. Denning, D. W. Global incidence and mortality of severe fungal disease. Lancet Infect. Dis. 24, e428–e438 (2024).

    Article  PubMed  Google Scholar 

  3. Zhang, F. et al. A marine microbiome antifungal targets urgent-threat drug-resistant fungi. Science 370, 974–978 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fisher, M. C. et al. Tackling the emerging threat of antifungal resistance to human health. Nat. Rev. Microbiol. 20, 557–571 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hancock, R. E. W. & Sahl, H.-G. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat. Biotechnol. 24, 1551–1557 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Homer, J. A., Johnson, R. M., Koelln, R. A., Moorhouse, A. D. & Moses, J. E. Strategic re-engineering of antibiotics. Nat. Rev. Bioeng. 3, 213–229 (2025).

    Article  CAS  PubMed  Google Scholar 

  7. Fisher, M. C., Hawkins, N. J., Sanglard, D. & Gurr, S. J. Worldwide emergence of resistance to antifungal drugs challenges human health and food security. Science 360, 739–742 (2018).

    Article  CAS  PubMed  Google Scholar 

  8. Ho, C. S. et al. Antimicrobial resistance: a concise update. Lancet Microbe 6, 100947 (2025).

    Article  PubMed  Google Scholar 

  9. Xiong, M. et al. Helical antimicrobial polypeptides with radial amphiphilicity. Proc. Natl Acad. Sci. USA 112, 13155–13160 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Li, X. et al. Supramolecular antibacterial materials for combatting antibiotic resistance. Adv. Mater. 31, e1805092 (2019).

    Article  PubMed  Google Scholar 

  11. Kong, H. et al. Development of aromatic-linked diamino acid antimicrobial peptide mimics with low hemolytic toxicity and excellent activity against methicillin-resistant Staphylococcus aureus (MRSA). J. Med. Chem. 66, 7756–7771 (2023).

    Article  CAS  PubMed  Google Scholar 

  12. Ghosh, C., Sarkar, P., Issa, R. & Haldar, J. Alternatives to conventional antibiotics in the era of antimicrobial resistance. Trends Microbiol. 27, 323–338 (2019).

    Article  CAS  PubMed  Google Scholar 

  13. Lehar, J. et al. Synergistic drug combinations tend to improve therapeutically relevant selectivity. Nat. Biotechnol. 27, 659–666 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Brochado, A. R. et al. Species-specific activity of antibacterial drug combinations. Nature 559, 259–263 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Si, Z., Pethe, K. & Chan-Park, M. B. Chemical basis of combination therapy to combat antibiotic resistance. JACS Au 3, 276–292 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ding, X. et al. A macromolecule reversing antibiotic resistance phenotype and repurposing drugs as potent antibiotics. Adv. Sci. 7, 2001374 (2020).

    Article  CAS  Google Scholar 

  17. Si, Z. et al. A glycosylated cationic block poly(β-peptide) reverses intrinsic antibiotic resistance in all ESKAPE Gram-negative bacteria. Angew. Chem. Int. Ed. 59, 6819–6826 (2020).

    Article  CAS  Google Scholar 

  18. Gong, Y., Wang, H. & Sun, J. AMP-mimetic antimicrobial polymer-involved synergic therapy with various coagents for improved efficiency. Biomacromolecules 25, 4619–4638 (2024).

    Article  CAS  PubMed  Google Scholar 

  19. Schmidt, N. W. et al. Engineering persister-specific antibiotics with synergistic antimicrobial functions. ACS Nano 8, 8786–8793 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bai, H. et al. A supramolecular antibiotic switch for antibacterial regulation. Angew. Chem. Int. Ed. 54, 13208–13213 (2015).

    Article  CAS  Google Scholar 

  21. Liu, L. et al. Self-assembled cationic peptide nanoparticles as an efficient antimicrobial agent. Nat. Nanotechnol. 4, 457–463 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Jiang, W. et al. Peptide-mimicking poly(2-oxazoline)s possessing potent antifungal activity and BBB penetrating property to treat invasive infections and meningitis. J. Am. Chem. Soc. 145, 25753–25765 (2023).

    Article  CAS  PubMed  Google Scholar 

  23. Zhou, M. et al. A dual-targeting antifungal is effective against multidrug-resistant human fungal pathogens. Nat. Microbiol 9, 1325–1339 (2024).

    Article  CAS  PubMed  Google Scholar 

  24. Zhang, X. et al. Development of lipo-γ-AA peptides as potent antifungal agents. J. Med. Chem. 65, 8029–8039 (2022).

    Article  CAS  PubMed  Google Scholar 

  25. Liu, F. et al. Synergistic wall digestion and cuproptosis against fungal infections using lywallzyme-induced self-assembly of metal-phenolic nanoflowers. Nat. Commun. 15, 9004 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chen, L. et al. Brain glucose induces tolerance of Cryptococcus neoformans to amphotericin B during meningitis. Nat. Microbiol 9, 346–358 (2024).

    Article  PubMed  Google Scholar 

  27. Maji, A. et al. Tuning sterol extraction kinetics yields a renal-sparing polyene antifungal. Nature 623, 1079–1085 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bennett, J. E. et al. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptoccal meningitis. N. Engl. J. Med. 301, 126–131 (1979).

    Article  CAS  PubMed  Google Scholar 

  29. Beck, A., Goetsch, L., Dumontet, C. & Corvaia, N. Strategies and challenges for the next generation of antibody–drug conjugates. Nat. Rev. Drug Discov. 16, 315–337 (2017).

    Article  CAS  PubMed  Google Scholar 

  30. Li, X., et al. Multifunctional nanoparticle-mediated combining therapy for human diseases. Signal Transduct. Target. Ther. 9, 1 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Detappe, A. et al. Molecular bottlebrush prodrugs as mono- and triplex combination therapies for multiple myeloma. Nat. Nanotechnol. 18, 184–192 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sofias, A. M. & Lammers, T. Multidrug nanomedicine. Nat. Nanotechnol. 18, 104–106 (2023).

    Article  CAS  PubMed  Google Scholar 

  33. Cheng, T. et al. Green tea catechin-based complex micelles combined with doxorubicin to overcome cardiotoxicity and multidrug resistance. Theranostics 6, 1277–1292 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lancet, J. E. et al. CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 8, e481–e491 (2021).

    Article  CAS  PubMed  Google Scholar 

  35. Lancet, J. E. et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J. Clin. Oncol. 36, 2684–2692 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Li, Y. et al. Co-delivery of precisely prescribed multi-prodrug combination by an engineered nanocarrier enables efficient individualized cancer chemotherapy. Adv. Mater. 34, e2110490 (2022).

    Article  PubMed  Google Scholar 

  37. Zhang, R. X., Wong, H. L., Xue, H. Y., Eoh, J. Y. & Wu, X. Y. Nanomedicine of synergistic drug combinations for cancer therapy—strategies and perspectives. J. Control. Release 240, 489–503 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhou, M. et al. Poly(2-oxazoline)-based functional peptide mimics: eradicating MRSA infections and persisters while alleviating antimicrobial resistance. Angew. Chem. Int. Ed. 59, 6412–6419 (2020).

    Article  CAS  Google Scholar 

  39. Tauhardt, L., Kempe, K., Gottschaldt, M. & Schubert, U. S. Poly(2-oxazoline) functionalized surfaces: from modification to application. Chem. Soc. Rev. 42, 7998–8011 (2013).

    Article  CAS  PubMed  Google Scholar 

  40. Lorson, T. et al. Poly(2-oxazoline)s based biomaterials: a comprehensive and critical update. Biomaterials 178, 204–280 (2018).

    Article  CAS  PubMed  Google Scholar 

  41. Zhu, Y., Yang, B., Chen, S. & Du, J. Polymer vesicles: mechanism, preparation, application, and responsive behavior. Prog. Polym. Sci. 64, 1–22 (2017).

    Article  CAS  Google Scholar 

  42. Cui, H., Webber, M. J. & Stupp, S. I. Self-assembly of peptide amphiphiles: from molecules to nanostructures to biomaterials. Biopolymers 94, 1–18 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhang, Z., Ai, S., Yang, Z. & Li, X. Peptide-based supramolecular hydrogels for local drug delivery. Adv. Drug Deliv. Rev. 174, 482–503 (2021).

    Article  CAS  PubMed  Google Scholar 

  44. Walker, L. et al. The viscoelastic properties of the fungal cell wall allow traffic of AmBisome as intact liposome vesicles. mBio 9, e02383-17 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Colombo, R. & Rich, J. R. The therapeutic window of antibody drug conjugates: a dogma in need of revision. Cancer Cell 40, 1255–1263 (2022).

    Article  CAS  PubMed  Google Scholar 

  46. Yongvongsoontorn, N. et al. Carrier-enhanced anticancer efficacy of sunitinib-loaded green tea-based micellar nanocomplex beyond tumor-targeted delivery. ACS Nano 13, 7591–7602 (2019).

    Article  CAS  PubMed  Google Scholar 

  47. Wang, C. H., Wang, W. T. & Hsiue, G. H. Development of polyion complex micelles for encapsulating and delivering amphotericin B. Biomaterials 30, 3352–3358 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Laconde, G., Amblard, M. & Martinez, J. Synthesis of α-amino acid N-carboxyanhydrides. Org. Lett. 23, 6412–6416 (2021).

    Article  CAS  PubMed  Google Scholar 

  49. Dos Reis, T. F., et al. A host defense peptide mimetic, brilacidin, potentiates caspofungin antifungal activity against human pathogenic fungi. Nat. Commun. 14, 2052 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Davis, S. A. et al. Nontoxic antimicrobials that evade drug resistance. Nat. Chem. Biol. 11, 481–487 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wilcock, B. C., Endo, M. M., Uno, B. E. & Burke, M. D. C2′-OH of amphotericin B plays an important role in binding the primary sterol of human cells but not yeast cells. J. Am. Chem. Soc. 135, 8488–8491 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Liu, Y. -g, et al. NLRP3 inflammasome activation mediates radiation-induced pyroptosis in bone marrow-derived macrophages. Cell Death Dis. 8, e2579 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wiradharma, N., Tong, Y. W. & Yang, Y. Y. Self-assembled oligopeptide nanostructures for co-delivery of drug and gene with synergistic therapeutic effect. Biomaterials 30, 3100–3109 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Jiang, W. et al. Short guanidinium-functionalized poly(2-oxazoline)s displaying potent therapeutic efficacy on drug-resistant fungal infections. Angew. Chem. Int. Ed. 61, e202200778 (2022).

    Article  CAS  Google Scholar 

  55. Mukherjee, J., Pirofski, L. A., Scharff, M. D. & Casadevall, A. Antibody-mediated protection in mice with lethal intracerebral Cryptococcus neoformans infection. Proc. Natl Acad. Sci. USA 90, 3636–3640 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jafari, H. S. et al. Effects of antifungal therapy on inflammation, sterilization, and histology in experimental Candida albicans meningitis. Antimicrob. Agents Chemother. 38, 83–89 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research was supported by the Chinese Academy of Sciences Project for Young Scientists in Basic Research (YSBR-111, to R.L.), the National Natural Science Foundation of China (T2325010, to R.L.; 22475069 and 52203162, to Y.W.; 22305082, to M.Z.), the National Key Research and Development Program of China (2022YFC2303100, to R.L.), the Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism (Shanghai Municipal Education Commission) and the Open Research Fund of State Key Laboratory of Polymer Physics and Chemistry (Changchun Institute of Applied Chemistry, Chinese Academy of Sciences). We thank Research Center of Analysis and Test of East China University of Science and Technology and the Analysis and Testing Center of School of Chemical Engineering at East China University of Science and Technology for support with the characterization. We thank the staff members of the Integrated Laser Microscopy System at the National Facility for Protein Science in Shanghai, Zhangjiang Lab for providing technical support and assistance in data collection and analysis.

Author information

Author notes

  1. Qiang Zhang

    Present address: School of Chemistry and Chemical Engineering Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, Shanghai, 200240, China

  2. These authors contributed equally: Longqiang Liu, Min Zhou.

Authors and Affiliations

  1. State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China

    Longqiang Liu, Min Zhou & Runhui Liu

  2. Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China

    Ximian Xiao, Zihao Cong, Jiayang Xie, Junyu Zhang, Weinan Jiang & Runhui Liu

  3. Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Key Laboratory for Ultrafine Materials of Ministry of Education, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Engineering Research Center for Biomedical Materials of Ministry of Education, Key Laboratory of Specially Functional Polymeric Materials and Related Technology (Ministry of Education), School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, China

    Zihao Cong, Yueming Wu, Qiang Zhang, Junyu Zhang & Runhui Liu

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Contributions

R.L. directed the whole project and conceptualized the study. R.L., M.Z. and L.L. proposed the strategy, designed the experiments, evaluated the data and wrote the paper. L.L. performed the majority of the experiments. Q.Z. contributed to the preparation of antifungal micelles. L.L., X.X., J.Z. and J.X. contributed to the in vitro antifungal study. L.L., Z.C., X.X.and J.X. contributed to the in vivo study. M.Z. and Y.W. contributed to the data analysis and discussion of the results. All authors proofread the paper.

Corresponding author

Correspondence to Runhui Liu.

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Competing interests

R.L. and M.Z. are coinventors on a patent application covering the reported synthesis of poly(2-oxazoline)s and their antifungal application. R.L. and L.L. are also coinventors on a patent application covering the reported application of poly(2-oxazoline)s in drug delivery. The other authors declare no competing interests.

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Extended data

Extended Data Fig. 1 Structural characterization and reproducibility of block copolymers PGlyX-b-PNapY.

(a) Structural of poly(2-oxazoline)s block copolymers. (b) Summary of GPC characterization. Mn, number average molecular weight. Ð is the dispersity index. DP is the obtained degree of polymerization. (c) 1H NMR spectra of block poly(2-oxazoline)s in DMSO-D6, 400 MHz. (d) GPC traces of PGly6-b-PNap14 from 6 batches at the side chain NH-Boc protected stage. (e) Summary of GPC characterization. (f) The MIC values of PGly6-b-PNap14 from 6 batches.

Source data

Extended Data Fig. 2 The particle size and critical micelle concentration of polymer micelles.

(a) DLS measurement of the Size distribution of polymer micelles is indicated by spline fits. (b) The CMC of polymer micelles.

Source data

Extended Data Fig. 3 The synergistic effect of polymer micelles and AmB.

(a-k) The synergistic effect of polymer micelles and AmB against C. albicans, C. neoformans, C. glabrata and C. parapsilosis. The blue zone represents fungal growth visible to the naked eye, and the white zone represents complete fungal growth inhibition invisible to the naked eye. The star symbol represents the position of FICI value.

Extended Data Fig. 4 The fungal pathogen targeting ability of micelles.

(a-c) Distribution of AmBisome liposomes and micelles in a cells and fungi coculture mixture. (d-e) Distribution of micelles in a coculture mixture of Human umbilical vein endothelial cells (HUVEC, primary cells) and fungi, and Bone marrow-derived macrophages (BMDM, primary cells) and fungi.

Extended Data Fig. 5 The characterization and pathogen targeting studies of a series of polymeric micelles.

(a-b) Summary of GPC characterization. (c) GPC traces of of (PGlyaPEOzb)6-b-PNapY from 6 batches at the side chain NH-Boc protected stage. (d) DLS measurements and TEM images of micelles assembled from polymer (PGlyaPEOzb)6-b-PNapY. The scale bars in TEM images all represent 200 nm. (e-f) Distribution of AmBisome liposomes and micelles in a mammalian cells (NIH/3T3) and fungi (C. albicans) coculture mixture.

Source data

Extended Data Fig. 6 The loading capacity of polymer micelles.

(a) The water solubility of AmB and AmBmicelles. (b-c) MIC and FICI values of AmB in AmBmicelles and the mixture of AmB and micelles. (d) Normalized DLS measurements of the Size distribution of AmB and AmBmicelles are indicated by spline fits. (e) UV-vis spectra of AmB in H2O, AmB in DMSO, micelles and AmBmicelles. (f) The stability of AmBmicelles over two weeks at 4 oC. (g) The release kinetics of AmB in vitro at 37 oC. (h) The emission wavelength of nile red and nile red encapsulated in micelles in water under 559 nm excitation.

Source data

Extended Data Fig. 7 Pharmacokinetics and in vivo distribution of micelles and AmB in AmBmicelles.

(a) Structure of PGly4-b-PNap16-FITC. (b) Normalized DLS measurements of the Size distribution of AmBmicelles and AmBmicelles-FITC are indicated by spline fits. (c-d) Pharmacokinetics curve of micelles and AmB. (e-g) Distribution of micelles and AmB in different organs. The concentration ratios of micelles and AmB in different organs are listed at the top of the graph. The data are expressed as mean±s.d. n = 3 biologically independent animals.

Source data

Extended Data Fig. 8 The in vivo immunogenicity and toxicity of micelles and AmBmicelles.

(a) Cytokine profiling for serum after daily intravenous injection of micelles, AmBmicelles and saline, respectively, for 4 consecutive days. The mouse cytokine array coordinates are shown in Table S1. (b) Gray values of cytokine and chemokine expression. (c) The concentration of C3a in serum after daily intravenous injection of micelles, AmBmicelles and saline, respectively, for 4 consecutive days (n = 4 biologically independent animals). Data are presented as mean values ± s.d. Statistical analysis was conducted using one-way ANOVA with multiple comparisons using Tukey’s post-test.

Source data

Extended Data Fig. 9 The therapeutic efficacy of micelles and AmBmicelles in systemic candidiasis infection.

(a) Schematic diagram of an in vivo antifungal study. Survival ratio (b) and fungal cell burden in different organs (c) of mice with systemic fungal infection after treatment with saline (200 μL), micelles (15 mg/kg), and micelles (30 mg/kg), respectively. (n = 6 biologically independent animals). Data are presented as mean values ± s.d. Statistical analysis was conducted using one-way ANOVA with multiple comparisons using Tukey’s post hoc test. (d-e) Survival ratio and fungal cell burden in different organs of mice with systemic fungal infection after treatment with Saline (200 μL), AmB@PIC micelles (0.5 mg/kg), AmBisome (0.5 mg/kg, 1 mg/kg, 2 mg/kg, 4 mg/kg) and AmBmicelles (0.5 mg/kg) (n = 6 biologically independent animals). The concentration indicated is the concentration of AmB encapsulated by micelles. Data are presented as mean values ± s.d. Statistical analysis was conducted using one-way ANOVA with multiple comparisons using Tukey’s post hoc test.

Source data

Extended Data Fig. 10 Brain tissue slices and fungal cell burden in the brains of mice infected with fungal meningitis.

(a) Representative histological images from Grocott hexamine-silver stain of early treatment models of meningitis mouse brain at 15 and 22 days after infection treated with AmBmicelles (1 mg/kg AmB), AmBisome + 5FC (1 mg/kg AmB and 75 mg/kg 5FC), and Saline, respectively. Black arrows indicate the vesicular lesions in brain. (b) The fungal cell burden in mouse brains at 1 and 3 days after infection. (n = 6 biologically independent animals). Data are presented as mean values ± s.d. Statistical analysis was conducted using two tailed Student’s t test.

Source data

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Liu, L., Zhou, M., Xiao, X. et al. Effective combinatorial antifungal therapy using a host defense peptide mimic that self-assembles into delivery micelles. Nat Biotechnol (2026). https://doi.org/10.1038/s41587-025-02930-3

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