Antimicrobial peptide delivery to lung as peptibody mRNA in anti-inflammatory lipids treats multidrug-resistant bacterial pneumonia

  • Metlay, J. P. et al. Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am. J. Respir. Crit. Care Med. 200, e45–e67 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pragman, A. A., Berger, J. P. & Williams, B. J. Understanding persistent bacterial lung infections: clinical implications informed by the biology of the microbiota and biofilms. Clin. Pulm. Med. 23, 57–66 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mettelman, R. C., Allen, E. K. & Thomas, P. G. Mucosal immune responses to infection and vaccination in the respiratory tract. Immunity 55, 749–780 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hewitt, R. J. & Lloyd, C. M. Regulation of immune responses by the airway epithelial cell landscape. Nat. Rev. Immunol. 21, 347–362 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cookson, W. O., Cox, M. J. & Moffatt, M. F. New opportunities for managing acute and chronic lung infections. Nat. Rev. Microbiol. 16, 111–120 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Parmanik, A. et al. Current treatment strategies against multidrug-resistant bacteria: a review. Curr. Microbiol. 79, 388 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Grief, S. N. & Loza, J. K. Guidelines for the evaluation and treatment of pneumonia. Prim. Care: Clin. Off. Pract. 45, 485–503 (2018).

    Article 

    Google Scholar
     

  • Kellum, J. A. et al. Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the genetic and inflammatory markers of sepsis (GenIMS) study. Arch. Intern. Med. 167, 1655–1663 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kumar, V. Pulmonary innate immune response determines the outcome of inflammation during pneumonia and sepsis-associated acute lung injury. Front. Immunol. 11, 1722 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mookherjee, N., Anderson, M. A., Haagsman, H. P. & Davidson, D. J. Antimicrobial host defence peptides: functions and clinical potential. Nat. Rev. Drug Discov. 19, 311–332 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dijksteel, G. S., Ulrich, M. M., Middelkoop, E. & Boekema, B. K. Lessons learned from clinical trials using antimicrobial peptides (AMPs). Front. Microbiol. 12, 616979 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Izadpanah, A. & Gallo, R. L. Antimicrobial peptides. J. Am. Acad. Dermatol. 52, 381–390 (2005).

    Article 
    PubMed 

    Google Scholar
     

  • Zhang, L.-j. & Gallo, R. L. Antimicrobial peptides. Curr. Biol. 26, R14–R19 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Di, Y. P., Kuhn, J. M. & Mangoni, M. L. Lung antimicrobial proteins and peptides: from host defense to therapeutic strategies. Physiol. Rev. 104, 1643–1677 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mahlapuu, M., Björn, C. & Ekblom, J. Antimicrobial peptides as therapeutic agents: opportunities and challenges. Crit. Rev. Biotechnol. 40, 978–992 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hou, X. et al. Vitamin lipid nanoparticles enable adoptive macrophage transfer for the treatment of multidrug-resistant bacterial sepsis. Nat. Nanotechnol. 15, 41–46 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Steinstraesser, L. et al. Skin electroporation of a plasmid encoding hCAP-18/LL-37 host defense peptide promotes wound healing. Mol. Ther. 22, 734–742 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pyzik, M., Kozicky, L. K., Gandhi, A. K. & Blumberg, R. S. The therapeutic age of the neonatal Fc receptor. Nat. Rev. Immunol. 23, 415–432 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Czajkowsky, D. M., Hu, J., Shao, Z. & Pleass, R. J. Fc-fusion proteins: new developments and future perspectives. EMBO Mol. Med. 4, 1015–1028 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Levin, D., Golding, B., Strome, S. E. & Sauna, Z. E. Fc fusion as a platform technology: potential for modulating immunogenicity. Trends Biotechnol. 33, 27–34 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dürr, U. H., Sudheendra, U. S. & Ramamoorthy, A. LL-37, the only human member of the cathelicidin family of antimicrobial peptides. Biochim. Biophys. Acta 1758, 1408–1425 (2006).

    Article 
    PubMed 

    Google Scholar
     

  • Sørensen, O. E. et al. Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3. Blood 97, 3951–3959 (2001).

    Article 
    PubMed 

    Google Scholar
     

  • Park, M. D., Silvin, A., Ginhoux, F. & Merad, M. Macrophages in health and disease. Cell 185, 4259–4279 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rosales, C. & Uribe-Querol, E. Phagocytosis: a fundamental process in immunity. BioMed. Res. Int. 2017, 9042851 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nimmerjahn, F. & Ravetch, J. V. Fcγ receptors as regulators of immune responses. Nat. Rev. Immunol. 8, 34–47 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Uribe-Querol, E. & Rosales, C. Phagocytosis: our current understanding of a universal biological process. Front. Immunol. 11, 1066 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Herrero-Cervera, A., Soehnlein, O. & Kenne, E. Neutrophils in chronic inflammatory diseases. Cell. Mol. Immunol. 19, 177–191 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mittal, M., Siddiqui, M. R., Tran, K., Reddy, S. P. & Malik, A. B. Reactive oxygen species in inflammation and tissue injury. Antioxid. Redox Signal. 20, 1126–1167 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Saxton, R. A., Glassman, C. R. & Garcia, K. C. Emerging principles of cytokine pharmacology and therapeutics. Nat. Rev. Drug Discov. 22, 21–37 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Huang, X., He, D., Pan, Z., Luo, G. & Deng, J. Reactive-oxygen-species-scavenging nanomaterials for resolving inflammation. Mater. Today Bio 11, 100124 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, S. et al. Accelerating diabetic wound healing by ROS-scavenging lipid nanoparticle–mRNA formulation. Proc. Natl Acad. Sci. USA 121, e2322935121 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, F. et al. Nanoparticle-modified microrobots for in vivo antibiotic delivery to treat acute bacterial pneumonia. Nat. Mater. 21, 1324–1332 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Maciá, M. D. et al. Efficacy and potential for resistance selection of antipseudomonal treatments in a mouse model of lung infection by hypermutable Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 50, 975–983 (2006).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, A. S. et al. Methicillin-resistant Staphylococcus aureus. Nat. Rev. Dis. Prim. 4, 18033 (2018).

    Article 
    PubMed 

    Google Scholar
     

  • Zeng, C. et al. Leveraging mRNA sequences and nanoparticles to deliver SARS-CoV-2 antigens in vivo. Adv. Mater. 32, 2004452 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Chen, R. et al. Engineering circular RNA for enhanced protein production. Nat. Biotechnol. 41, 262–272 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, C. et al. Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system. Nat. Mater. 24, 1653–1663 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kim, M. et al. Dual SORT LNPs for multi-organ base editing. Nat. Biotechnol. https://doi.org/10.1038/s41587-025-02675-z (2025).

  • Devkota, S. P., Onah, C., Joshi, P. R., Adhikari, S. & Baral, P. Optimized method for higher yield of alveolar macrophage isolation for ex vivo studies. Heliyon 10, e37221 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xue, Y. et al. LNP–RNA-mediated antigen presentation leverages SARS-CoV-2-specific immunity for cancer treatment. Nat. Commun. 16, 2198 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, S. et al. Nanotechnology-based mRNA vaccines. Nat. Rev. Methods Prim. 3, 63 (2023).

    Article 
    CAS 

    Google Scholar
     

  • Mukherjee, A. et al. Engineered mutant α-ENaC subunit mRNA delivered by lipid nanoparticles reduces amiloride currents in cystic fibrosis-based cell and mice models. Sci. Adv. 6, eabc5911 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Witten, J. et al. Artificial intelligence-guided design of lipid nanoparticles for pulmonary gene therapy. Nat. Biotechnol. https://doi.org/10.1038/s41587-024-02490-y (2024).

  • Kim, J. et al. Engineering lipid nanoparticles for enhanced intracellular delivery of mrna through inhalation. ACS Nano 16, 14792–14806 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sun, Y. et al. In vivo editing of lung stem cells for durable gene correction in mice. Science 384, 1196–1202 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Facchini, M., De Fino, I., Riva, C. & Bragonzi, A. Long term chronic Pseudomonas aeruginosa airway infection in mice. J. Vis. Exp. 85, 51019 (2014).


    Google Scholar
     

  • van den Berg, E. et al. Role of the Fas/FasL system in a model of RSV infection in mechanically ventilated mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 301, L451–L460 (2011).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Leave a Comment