Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Basic Science Article
  • Published:

Combined transamniotic delivery of surfactant proteins B and C mRNA enhances preterm fetal surfactant production in a rodent model

Pediatric Research (2025)Cite this article

Abstract

Background

Prematurity remains the leading cause of neonatal mortality and morbidity, largely due to pulmonary surfactant deficiency. We compared isolated and combined transamniotic delivery of surfactant proteins B (SPB) and C (SPC) mRNA.

Methods

Fetuses (n = 415) from thirty-two time-dated dams underwent intra-amniotic injections on gestational day 17 (E17, term= E21-22) of lipopolyplex-encapsulated mRNA consisting of either human SPB (hSPB) mRNA (n = 151), human SPC (hSPC) mRNA (n = 102), a combination of hSPB+hSPC mRNA (n = 113), or lipopolyplex without mRNA (n = 49). Fetal lungs were screened for hSPB and hSPC by ELISA daily until term. Phosphatidylcholine was measured in the amniotic fluid.

Results

Controlled by mRNA-free injections, the hSPB protein was detected in the SPB mRNA group only at E18 and E19, whereas in the SPB + SPC mRNA group it was detected at every preterm timepoint (E18-E20), either separately or combined (p < 0.001 for all). The hSPC protein was detected in the SPC mRNA group only at E18 (p = 0.015). Amniotic fluid phosphatidylcholine was significantly increased in the SPC mRNA and SPB + SPC mRNA groups compared to controls (p < 0.001).

Conclusions

Combined transamniotic delivery of exogenous mRNA encoding for SPB and SPC enhances surfactant production prior to term when compared with isolated mRNA administrations in a healthy rat model.

Impact

  • Transamniotic mRNA delivery may become a novel strategy for surfactant replacement therapy.

  • Combined transamniotic mRNA delivery for surfactant proteins B and C enhances preterm surfactant production.

  • Transamniotic mRNA delivery can be achieved in a short time frame, for example compatible with select clinical settings of preterm labor.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Overview of the experimental protocol depicting the 4 groups of intra-amniotic injections - 3 groups with different pulmonary surfactant mRNA compositions and 1 control group with the encapsulation composite lacking any mRNA - as well as the analyses performed at multiple time points thereafter.
Fig. 2: Pulmonary surfactant levels at different time points.
Fig. 3: Phosphatidylcholine levels in fetal rat amniotic fluid at E18 to E21, preterm (combined E18-E20), and term (E21) for mRNA groups and controls.

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Daniels, C. B. & Orgeig, S. Pulmonary surfactant: the key to the evolution of air breathing. N. Physiol. Sci. 18, 151–157 (2003).

    CAS  Google Scholar 

  2. Magni, T. et al. Health economic studies of surfactant replacement therapy in neonates with respiratory distress syndrome: a systematic literature review. Pharmacoecon. Open 7, 359–371 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Nogee, L. M. Alterations in Sp-B and Sp-C expression in neonatal lung disease. Annu Rev. Physiol. 66, 601–623 (2004).

    Article  PubMed  CAS  Google Scholar 

  4. Hamvas, A. Inherited surfactant protein-B deficiency and surfactant protein-C associated disease: clinical features and evaluation. Semin Perinatol. 30, 316–326 (2006).

    Article  PubMed  Google Scholar 

  5. Hamvas, A. et al. Surfactant protein B deficiency: antenatal diagnosis and prospective treatment with surfactant replacement. J. Pediatr. 125, 356–361 (1994).

    Article  PubMed  CAS  Google Scholar 

  6. Walther, F. J., Waring, A. J., Sherman, M. A., Zasadzinski, J. A. & Gordon, L. M. Hydrophobic surfactant proteins and their analogues. Neonatology 91, 303–310 (2007).

    Article  PubMed  CAS  Google Scholar 

  7. Damase, T. R. et al. The limitless future of RNA therapeutics. Front. Bioeng. Biotechnol. 9, 628137 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Kowalski, P. S., Rudra, A., Miao, L. & Anderson, D. G. Delivering the messenger: advances in technologies for therapeutic mRNA delivery. Mol. Ther. J. Am. Soc. Gene Ther. 27, 710–728 (2019).

    Article  CAS  Google Scholar 

  9. Moskowitzova, K., Naus, A. E., Dang, T. T., Zurakowski, D. & Fauza, D. O. Transamniotic delivery of surfactant protein B mRNA in a healthy model. Fetal Diagn. Ther. 52, 148–154 (2025).

  10. Moskowitzova, K., Whitlock, A. E., Zurakowski, D. & Fauza, D. O. Hematogenous routing of exogenous messenger rna delivered into the amniotic fluid. J. Surg. Res. 289, 116–120 (2023).

    Article  PubMed  CAS  Google Scholar 

  11. Moskowitzova, K. et al. Perinatal vaccination by transamniotic fetal mRNA delivery: immunization against human cytomegalovirus in a rodent model. J. Pediatr. Surg. 60, 161956 (2025).

    Article  PubMed  Google Scholar 

  12. Agassandian, M. & Mallampalli, R. K. Surfactant phospholipid metabolism. Biochim Biophys. Acta 1831, 612–625 (2013).

    Article  PubMed  CAS  Google Scholar 

  13. Pioselli, B. et al. Pulmonary surfactant: a unique biomaterial with life-saving therapeutic applications. Curr. Med Chem. 29, 526–590 (2022).

    Article  PubMed  CAS  Google Scholar 

  14. Lamberska, T. et al. Oropharyngeal surfactant can improve initial stabilisation and reduce rescue intubation in infants born below 25 weeks of gestation. Acta Paediatr. 107, 73–78 (2018).

    Article  PubMed  CAS  Google Scholar 

  15. Bahadue, F. L. & Soll, R. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database Syst. Rev. 11, CD001456 (2012).

    PubMed  Google Scholar 

  16. Hentschel, R., Bohlin, K., van Kaam, A., Fuchs, H. & Danhaive, O. Surfactant replacement therapy: from biological basis to current clinical practice. Pediatr. Res 88, 176–183 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Mazela, J., Merritt, T. A., Gadzinowski, J. & Sinha, S. Evolution of pulmonary surfactants for the treatment of neonatal respiratory distress syndrome and paediatric lung diseases. Acta Paediatr. 95, 1036–1048 (2006).

    Article  PubMed  Google Scholar 

  18. Almlen, A. et al. Surfactant proteins B and C are both necessary for alveolar stability at end expiration in premature rabbits with respiratory distress syndrome. J. Appl Physiol. (1985) 104, 1101–1108 (2008).

    Article  PubMed  CAS  Google Scholar 

  19. Almlen, A. et al. Synthetic surfactant based on analogues of Sp-B and Sp-C is superior to single-peptide surfactants in ventilated premature rabbits. Neonatology 98, 91–99 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Sweet, D. G. et al. A first-in-human clinical study of a new Sp-B and Sp-C enriched synthetic surfactant (Chf5633) in preterm babies with respiratory distress syndrome: two-year outcomes. J. Matern Fetal Neonatal Med. 35, 4739–4742 (2022).

    Article  PubMed  CAS  Google Scholar 

  21. Jiang, Y. et al. A “top-down” approach to actuate poly(amine-co-ester) terpolymers for potent and safe mRNA delivery. Biomaterials 176, 122–130 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. To, K. K. W. & Cho, W. C. S. An overview of rational design of mRNA-based therapeutics and vaccines. Expert Opin. drug Discov. 16, 1307–1317 (2021).

    Article  PubMed  CAS  Google Scholar 

  23. Haagsman, H. P. & Diemel, R. V. Surfactant-associated proteins: functions and structural variation. Comp. Biochem Physiol. A Mol. Integr. Physiol. 129, 91–108 (2001).

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

This work was funded by the Kevin and Kate McCarey Fund for Surgical Research at Boston Children’s Hospital. The funding source had no role in the study design, data collection or analysis, writing of this report, or the decision to submit this article for presentation/publication.

Author information

Authors and Affiliations

  1. Department of Surgery, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    Kamila Moskowitzova, Emily M. Scire, Tanya T. Dang, Beatriz S. Bechara, Eva Zacharakis, Ayaka Aihara, David Zurakowski & Dario O. Fauza

Authors
  1. Kamila Moskowitzova
    View author publications

    Search author on:PubMed Google Scholar

  2. Emily M. Scire
    View author publications

    Search author on:PubMed Google Scholar

  3. Tanya T. Dang
    View author publications

    Search author on:PubMed Google Scholar

  4. Beatriz S. Bechara
    View author publications

    Search author on:PubMed Google Scholar

  5. Eva Zacharakis
    View author publications

    Search author on:PubMed Google Scholar

  6. Ayaka Aihara
    View author publications

    Search author on:PubMed Google Scholar

  7. David Zurakowski
    View author publications

    Search author on:PubMed Google Scholar

  8. Dario O. Fauza
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Study conception and design: Kamila Moskowitzova, Dario O Fauza. Data acquisition: Kamila Moskowitzova, Emily M Scire, Tanya T Dang, Beatriz S Bechara, Eva Zacharakis, Ayaka Aihara. Analysis and data interpretation: Kamila Moskowitzova, David Zurakowski, Dario O Fauza. Drafting of the manuscript: Kamila Moskowitzova, David Zurakowski, Dario O Fauza. Critical revision: Kamila Moskowitzova, Dario O Fauza.

Corresponding author

Correspondence to Dario O. Fauza.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Moskowitzova, K., Scire, E.M., Dang, T.T. et al. Combined transamniotic delivery of surfactant proteins B and C mRNA enhances preterm fetal surfactant production in a rodent model. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04493-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41390-025-04493-0

Search

Advanced search

Quick links