Limiting endosomal damage sensing reduces inflammation triggered by lipid nanoparticle endosomal escape

Posted on
limiting-endosomal-damage-sensing-reduces-inflammation-triggered-by-lipid-nanoparticle-endosomal-escape
Limiting endosomal damage sensing reduces inflammation triggered by lipid nanoparticle endosomal escape

Data availability

All quantitative data used for plots in main figures are available in the Source Data file. Additional data are available upon reasonable request from the corresponding author. Source data are provided with this paper.

References

  1. Kon, E., Elia, U. & Peer, D. Principles for designing an optimal mRNA lipid nanoparticle vaccine. Curr. Opin. Biotechnol. 73, 329–336 (2022).

    PubMed  CAS  Google Scholar 

  2. Verma, M. et al. The landscape for lipid-nanoparticle-based genomic medicines. Nat. Rev. Drug Discov. 22, 349–350 (2023).

    PubMed  CAS  Google Scholar 

  3. Kiaie, S. H. et al. Recent advances in mRNA-LNP therapeutics: immunological and pharmacological aspects. J. Nanobiotechnol. 20, 276 (2022).

    CAS  Google Scholar 

  4. Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021).

    PubMed  CAS  Google Scholar 

  5. Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020).

    PubMed  CAS  Google Scholar 

  6. Parhiz, H. et al. Added to pre-existing inflammation, mRNA-lipid nanoparticles induce inflammation exacerbation (IE). J. Control. Release 344, 50–61 (2022).

    PubMed  CAS  Google Scholar 

  7. Tahtinen, S. et al. IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines. Nat. Immunol. 23, 532–542 (2022).

    PubMed  CAS  Google Scholar 

  8. Moghimi, S. M. & Simberg, D. Pro-inflammatory concerns with lipid nanoparticles. Mol. Ther. 30, 2109–2110 (2022).

    PubMed  PubMed Central  CAS  Google Scholar 

  9. Ndeupen, S. et al. The mRNA-LNP platform’s lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory. iScience 24, 103479 (2021).

    PubMed  PubMed Central  CAS  Google Scholar 

  10. Sharma, P., Hoorn, D., Aitha, A., Breier, D. & Peer, D. The immunostimulatory nature of mRNA lipid nanoparticles. Adv. Drug Deliv. Rev. 205, 115175 (2024).

    PubMed  CAS  Google Scholar 

  11. Connors, J. et al. Lipid nanoparticles (LNP) induce activation and maturation of antigen presenting cells in young and aged individuals. Commun. Biol. 6, 188 (2023).

    PubMed  PubMed Central  CAS  Google Scholar 

  12. Coelho, T. et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N. Engl. J. Med. 369, 819–829 (2013).

    PubMed  CAS  Google Scholar 

  13. Alameh, M.-G. et al. Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses. Immunity 55, 1136–1138 (2022).

    PubMed  PubMed Central  Google Scholar 

  14. Swaminathan, G. et al. A novel lipid nanoparticle adjuvant significantly enhances B cell and T cell responses to sub-unit vaccine antigens. Vaccine 34, 110–119 (2016).

    PubMed  CAS  Google Scholar 

  15. Pardi, N. et al. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J. Exp. Med. 215, 1571–1588 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  16. Zamani, P. et al. Characterization of stability, safety and immunogenicity of the mRNA lipid nanoparticle vaccine Iribovax® against COVID-19 in nonhuman primates. J. Control. Release 360, 316–334 (2023).

    PubMed  CAS  Google Scholar 

  17. Alameh, M.-G. et al. Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses. Immunity 54, 2877–2892.e7 (2021).

    PubMed  PubMed Central  CAS  Google Scholar 

  18. Lee, J., Woodruff, M. C., Kim, E. H. & Nam, J.-H. Knife’s edge: balancing immunogenicity and reactogenicity in mRNA vaccines. Exp. Mol. Med. 55, 1305–1313 (2023).

    PubMed  PubMed Central  CAS  Google Scholar 

  19. Hong, M.-H., Weng, I.-C., Li, F.-Y., Lin, W.-H. & Liu, F.-T. Intracellular galectins sense cytosolically exposed glycans as danger and mediate cellular responses. J. Biomed. Sci. 28, 16 (2021).

    PubMed  PubMed Central  CAS  Google Scholar 

  20. Liu, F.-T. & Stowell, S. R. The role of galectins in immunity and infection. Nat. Rev. Immunol. 23, 479–494 (2023).

    PubMed  CAS  Google Scholar 

  21. Scheffer, L. L. et al. Mechanism of Ca2+-triggered ESCRT assembly and regulation of cell membrane repair. Nat. Commun. 5, 5646 (2014).

    PubMed  CAS  Google Scholar 

  22. Vietri, M., Radulovic, M. & Stenmark, H. The many functions of ESCRTs. Nat. Rev. Mol. Cell Biol. 21, 25–42 (2020).

    PubMed  CAS  Google Scholar 

  23. Jimenez, A. J. et al. ESCRT machinery is required for plasma membrane repair. Science 343, 1247136 (2014).

    PubMed  Google Scholar 

  24. Skowyra, M. L., Schlesinger, P. H., Naismith, T. V. & Hanson, P. I. Triggered recruitment of ESCRT machinery promotes endolysosomal repair. Science 360, eaar5078 (2018).

    PubMed  PubMed Central  Google Scholar 

  25. Dong, Y. et al. Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates. Proc. Natl Acad. Sci. USA 111, 3955–3960 (2014).

    PubMed  PubMed Central  CAS  Google Scholar 

  26. Li, B. et al. Combinatorial design of nanoparticles for pulmonary mRNA delivery and genome editing. Nat. Biotechnol. 41, 1410–1415 (2023).

    PubMed  PubMed Central  CAS  Google Scholar 

  27. Jin, H. et al. Engineered lipid nanoparticles for the treatment of pulmonary fibrosis by regulating epithelial-mesenchymal transition in the lungs. Adv. Funct. Mater. 33, 2209432 (2023).

    CAS  Google Scholar 

  28. Ball, R. L., Hajj, K. A., Vizelman, J., Bajaj, P. & Whitehead, K. A. Lipid nanoparticle formulations for enhanced co-delivery of siRNA and mRNA. Nano Lett. 18, 3814–3822 (2018).

    PubMed  CAS  Google Scholar 

  29. Fink, S. L. & Cookson, B. T. Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect. Immun. 73, 1907–1916 (2005).

    PubMed  PubMed Central  CAS  Google Scholar 

  30. Eygeris, Y., Gupta, M., Kim, J. & Sahay, G. Chemistry of lipid nanoparticles for RNA delivery. Acc. Chem. Res. 55, 2–12 (2022).

    PubMed  CAS  Google Scholar 

  31. Liu, S. et al. Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR–Cas gene editing. Nat. Mater. 20, 701–710 (2021).

    PubMed  PubMed Central  CAS  Google Scholar 

  32. Schlich, M. et al. Cytosolic delivery of nucleic acids: the case of ionizable lipid nanoparticles. Bioeng. Transl. Med. 6, e10213 (2021).

    PubMed  PubMed Central  CAS  Google Scholar 

  33. Mok, K. W. & Cullis, P. R. Structural and fusogenic properties of cationic liposomes in the presence of plasmid DNA. Biophys. J. 73, 2534–2545 (1997).

    PubMed  PubMed Central  CAS  Google Scholar 

  34. Philipp, J. et al. pH-dependent structural transitions in cationic ionizable lipid mesophases are critical for lipid nanoparticle function. Proc. Natl Acad. Sci. USA 120, e2310491120 (2023).

    PubMed  PubMed Central  CAS  Google Scholar 

  35. Yu, H. et al. Inverse cubic and hexagonal mesophase evolution within ionizable lipid nanoparticles correlates with mRNA transfection in macrophages. J. Am. Chem. Soc. https://doi.org/10.1021/jacs.3c08729 (2023).

    PubMed  PubMed Central  Google Scholar 

  36. Semple, S. C. et al. Rational design of cationic lipids for siRNA delivery. Nat. Biotechnol. 28, 172–176 (2010).

    PubMed  CAS  Google Scholar 

  37. Akinc, A. et al. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nat. Biotechnol. 26, 561–569 (2008).

    PubMed  PubMed Central  CAS  Google Scholar 

  38. Han, X. et al. An ionizable lipid toolbox for RNA delivery. Nat. Commun. 12, 7233 (2021).

    PubMed  PubMed Central  CAS  Google Scholar 

  39. Lee, S. M. et al. A systematic study of unsaturation in lipid nanoparticles leads to improved mRNA transfection in vivo. Angew. Chem. Weinh. Bergstr. Ger. 133, 5912–5917 (2021).

    Google Scholar 

  40. Farbiak, L. et al. All-in-one dendrimer-based lipid nanoparticles enable precise HDR-mediated gene editing in vivo. Adv. Mater. 33, e2006619 (2021).

    PubMed  PubMed Central  Google Scholar 

  41. Hajj, K. A. et al. Branched-tail lipid nanoparticles potently deliver mRNA in vivo due to enhanced ionization at endosomal pH. Small 15, e1805097 (2019).

    PubMed  Google Scholar 

  42. Conus, S. & Simon, H.-U. Cathepsins: key modulators of cell death and inflammatory responses. Biochem. Pharmacol. 76, 1374–1382 (2008).

    PubMed  CAS  Google Scholar 

  43. Pierzyńska-Mach, A., Janowski, P. A. & Dobrucki, J. W. Evaluation of acridine orange, LysoTracker Red, and quinacrine as fluorescent probes for long-term tracking of acidic vesicles. Cytom. A 85, 729–737 (2014).

    Google Scholar 

  44. Repnik, U. et al. LLOMe does not release cysteine cathepsins to the cytosol but inactivates them in transiently permeabilized lysosomes. J. Cell Sci. 130, 3124–3140 (2017).

    PubMed  CAS  Google Scholar 

  45. Sahay, G. et al. Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling. Nat. Biotechnol. 31, 653–658 (2013).

    PubMed  PubMed Central  CAS  Google Scholar 

  46. Gilleron, J. et al. Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape. Nat. Biotechnol. 31, 638–646 (2013).

    PubMed  CAS  Google Scholar 

  47. Stewart, M. P. et al. Challenges in carrier-mediated intracellular delivery: moving beyond endosomal barriers. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 8, 465–478 (2016).

    PubMed  Google Scholar 

  48. Chatterjee, S., Kon, E., Sharma, P. & Peer, D. Endosomal escape: a bottleneck for LNP-mediated therapeutics. Proc. Natl Acad. Sci. USA 121, e2307800120 (2024).

    PubMed  PubMed Central  CAS  Google Scholar 

  49. Staring, J., Raaben, M. & Brummelkamp, T. R. Viral escape from endosomes and host detection at a glance. J. Cell Sci. 131, jcs216259 (2018).

    PubMed  Google Scholar 

  50. Daussy, C. F. & Wodrich, H. ‘Repair me if you can’: membrane damage, response, and control from the viral perspective. Cells 9, 2042 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

  51. Kilchrist, K. V. et al. Gal8 visualization of endosome disruption predicts carrier-mediated biologic drug intracellular bioavailability. ACS Nano 13, 1136–1152 (2019).

    PubMed  PubMed Central  CAS  Google Scholar 

  52. Wittrup, A. et al. Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown. Nat. Biotechnol. 33, 870–876 (2015).

    PubMed  PubMed Central  CAS  Google Scholar 

  53. Herrera, M., Kim, J., Eygeris, Y., Jozic, A. & Sahay, G. Illuminating endosomal escape of polymorphic lipid nanoparticles that boost mRNA delivery. Biomater. Sci. 9, 4289–4300 (2021).

    PubMed  PubMed Central  CAS  Google Scholar 

  54. Gupta, S., Bendjennat, M. & Saffarian, S. Abrogating ALIX interactions results in stuttering of the ESCRT machinery. Viruses 12, 1032 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

  55. Rühl, S. et al. ESCRT-dependent membrane repair negatively regulates pyroptosis downstream of GSDMD activation. Science 362, 956–960 (2018).

    PubMed  Google Scholar 

  56. Yang, Y., Wang, M., Zhang, Y.-Y., Zhao, S.-Z. & Gu, S. The endosomal sorting complex required for transport repairs the membrane to delay cell death. Front. Oncol. 12, 1007446 (2022).

    PubMed  PubMed Central  CAS  Google Scholar 

  57. Chen, Z. et al. Modular design of biodegradable ionizable lipids for improved mRNA delivery and precise cancer metastasis delineation in vivo. J. Am. Chem. Soc. 145, 24302–24314 (2023).

    PubMed  CAS  Google Scholar 

  58. Robinson, B. S. et al. The sweet-side of leukocytes: galectins as master regulators of neutrophil function. Front. Immunol. 10, 1762 (2019).

    PubMed  PubMed Central  CAS  Google Scholar 

  59. Kassab, G., Doran, K., Mo, Y. & Zheng, G. Inhalable gene therapy and the lung surfactant problem. Nano Lett. 23, 10099–10102 (2023).

    PubMed  CAS  Google Scholar 

  60. Tzotzos, S. J., Fischer, B., Fischer, H. & Zeitlinger, M. Incidence of ARDS and outcomes in hospitalized patients with COVID-19: a global literature survey. Crit. Care 24, 516 (2020).

    PubMed  PubMed Central  Google Scholar 

  61. Shih, L.-J. et al. An important call: suggestion of using IL-10 as therapeutic agent for COVID-19 with ARDS and other complications. Virulence 14, 2190650 (2023).

    PubMed  PubMed Central  Google Scholar 

  62. Parhiz, H. et al. PECAM-1 directed re-targeting of exogenous mRNA providing two orders of magnitude enhancement of vascular delivery and expression in lungs independent of apolipoprotein E-mediated uptake. J. Control. Release 291, 106–115 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  63. Wang, K. et al. Evaluation on redox-triggered degradation of thioether-bridged hybrid mesoporous organosilica nanoparticles. Colloids Surf. A 608, 125566 (2021).

    CAS  Google Scholar 

  64. van der Vlies, A. J. et al. Thioether-based polymeric micelles with fine-tuned oxidation sensitivities for chemotherapeutic drug delivery. Biomacromolecules 23, 77–88 (2022).

    PubMed  Google Scholar 

  65. Markovic, S. Galectin-3 plays an important pro-inflammatory role in the induction phase of acute colitis by promoting activation of NLRP3 inflammasome and production of IL-1β in macrophages. J. Crohns Colitis 10, 593–606 (2016).

    Google Scholar 

  66. Tian, J. et al. Galectin-3 regulates inflammasome activation in cholestatic liver injury. FASEB J. 30, 4202–4213 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  67. James, R. E. et al. Loss of galectin-3 decreases the number of immune cells in the subventricular zone and restores proliferation in a viral model of multiple sclerosis. Glia 64, 105–121 (2016).

    PubMed  Google Scholar 

  68. Nieminen, J., St-Pierre, C., Bhaumik, P., Poirier, F. & Sato, S. Role of galectin-3 in leukocyte recruitment in a murine model of lung infection by Streptococcus pneumoniae. J. Immunol. 180, 2466–2473 (2008).

    PubMed  CAS  Google Scholar 

  69. Snarr, B. D. et al. Galectin-3 enhances neutrophil motility and extravasation into the airways during Aspergillus fumigatus infection. PLoS Pathog. 16, e1008741 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

  70. Farnworth, S. L. et al. Galectin-3 reduces the severity of pneumococcal pneumonia by augmenting neutrophil function. Am. J. Pathol. 172, 395–405 (2008).

    PubMed  PubMed Central  CAS  Google Scholar 

  71. Humphries, D. C. et al. Selective myeloid depletion of galectin-3 offers protection against acute and chronic lung injury. Front. Pharmacol. 12, 715986 (2021).

    PubMed  PubMed Central  CAS  Google Scholar 

  72. Bhaumik, P., St-Pierre, G., Milot, V., St-Pierre, C. & Sato, S. Galectin-3 facilitates neutrophil recruitment as an innate immune response to a parasitic protozoa cutaneous infection. J. Immunol. 190, 630–640 (2013).

    PubMed  CAS  Google Scholar 

  73. Haley, R. M. et al. Lipid nanoparticle delivery of small proteins for potent in vivo RAS inhibition. ACS Appl. Mater. Interfaces 15, 21877–21892 (2023).

    PubMed  PubMed Central  CAS  Google Scholar 

  74. Sanjana, N. E., Shalem, O. & Zhang, F. Improved vectors and genome-wide libraries for CRISPR screening. Nat. Methods 11, 783–784 (2014).

    PubMed  PubMed Central  CAS  Google Scholar 

  75. Shalem, O. et al. Genome-scale CRISPR-Cas9 knockout screening in human cells. Science 343, 84–87 (2014).

    PubMed  CAS  Google Scholar 

  76. Doench, J. G. et al. Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9. Nat. Biotechnol. 34, 184–191 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  77. Sanson, K. R. et al. Optimized libraries for CRISPR-Cas9 genetic screens with multiple modalities. Nat. Commun. 9, 5416 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

Research reported in this publication was supported by the American Heart Association under grant 23PRE1014444 (to S.O.-L.) and grant 24PRE1195406 (to M.N.P.), NIH F31 fellowship (award number 1F31AG077874-01) (to M.L.A.), Ruth L. Kirschstein National Research Service Award (NRSA) F31HL154662 (to M.E.Z.), grant NIH R01 NS 131279 (to O.A.M.-C.), grant NIH R61DA058501, R01DA057337 (to P.J.G.), Pulmonary Fibrosis Foundation Tully Family Familial Pulmonary Fibrosis Research Award, grant 5K08HL150226 (to J.K.) and grant NIH R01 HL157189 (to V.R.M., J.W.M. and J.S.B.), and grants NIH R01HL153510, R01 HL60694, R01 HL164594 and R41 NS130812 (to J.S.B.).

Author information

Author notes

  1. These authors contributed equally: Serena Omo-Lamai, Yufei Wang, Manthan N. Patel.

Authors and Affiliations

  1. Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA

    Serena Omo-Lamai, Liuqian Wang, Fengyi Dong, Michael Tobin, Shruthi Murali, Liam S. Chase, Dennis Discher, Andrew Tsourkas & Jacob S. Brenner

  2. Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Yufei Wang, Manthan N. Patel, Carolann Espy, Oscar A. Marcos-Contreras, Jacob W. Myerson, Vladimir R. Muzykantov & Jacob S. Brenner

  3. Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA

    Aleksa Milosavljevic, Daniel Zuschlag & Dirk Trauner

  4. Division of Rheumatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Subhajit Poddar & Jonathan J. Miner

  5. Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Jichuan Wu, Aparajeeta Majumder, Eno-Obong Essien, Anit Shah, Jeremy Katzen & Jacob S. Brenner

  6. Emergency Medical Department, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Mengwen Shen

  7. Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA

    Breana Channer & Peter J. Gaskill

  8. Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Tyler E. Papp & Hamideh Parhiz

  9. Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA

    Rhea Maheshwari

  10. Department of Bioengineering, George R. Brown School of Engineering, Rice University, Houston, TX, USA

    Sumin Jeong

  11. Department of Chemical Engineering, School of Engineering and Applied Sciences, University of Virginia, Charlottesville, VA, USA

    Sofia Patel

  12. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Marco E. Zamora & Sunny Shin

  13. Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA

    Mariah L. Arral & Kathryn A. Whitehead

  14. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Christopher A. Hunter & Igor Brodsky

  15. Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA

    Kathryn A. Whitehead

Authors

  1. Serena Omo-Lamai
  2. Yufei Wang
  3. Manthan N. Patel
  4. Aleksa Milosavljevic
  5. Daniel Zuschlag
  6. Subhajit Poddar
  7. Jichuan Wu
  8. Liuqian Wang
  9. Fengyi Dong
  10. Carolann Espy
  11. Aparajeeta Majumder
  12. Eno-Obong Essien
  13. Mengwen Shen
  14. Breana Channer
  15. Tyler E. Papp
  16. Michael Tobin
  17. Rhea Maheshwari
  18. Sumin Jeong
  19. Sofia Patel
  20. Anit Shah
  21. Shruthi Murali
  22. Liam S. Chase
  23. Marco E. Zamora
  24. Mariah L. Arral
  25. Oscar A. Marcos-Contreras
  26. Jacob W. Myerson
  27. Christopher A. Hunter
  28. Dennis Discher
  29. Peter J. Gaskill
  30. Andrew Tsourkas
  31. Vladimir R. Muzykantov
  32. Igor Brodsky
  33. Sunny Shin
  34. Kathryn A. Whitehead
  35. Hamideh Parhiz
  36. Jeremy Katzen
  37. Jonathan J. Miner
  38. Dirk Trauner
  39. Jacob S. Brenner

Contributions

S.O.-L., Y.W. and M.N.P.: project administration, methodology, investigation, formal analysis, data curation, conceptualization, writing (review and editing) and writing (original draft). A. Milosavljevic, D.Z., S. Poddar, J.W., L.W., F.D., C.E., A. Majumder, E.-O.E., M.S., B.C., T.E.P., M.T., R.M., S.J., S. Patel, A.S., S.M., L.S.C., M.E.Z. and M.L.A.: methodology, investigation and data curation. O.A.M.-C., J.W.M., C.A.H., D.D., P.J.G., A.T., V.R.M., I.B., S.S., K.A.W., H.P., J.K., J.J.M. and D.T.: resources, methodology and supervision. J.S.B.: visualization, resources, methodology, funding acquisition, formal analysis, data curation, conceptualization, writing (review and editing) and supervision.

Corresponding author

Correspondence to Jacob S. Brenner.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Nanotechnology thanks Irene La-Beck, Harald Stenmark and Sean Stowell 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.

Supplementary information

Source data

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Omo-Lamai, S., Wang, Y., Patel, M.N. et al. Limiting endosomal damage sensing reduces inflammation triggered by lipid nanoparticle endosomal escape. Nat. Nanotechnol. (2025). https://doi.org/10.1038/s41565-025-01974-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41565-025-01974-5