Reply to Zeng: VEGF-based Therapy for Congenital Diaphragmatic Hernia: A Breakthrough or a Hidden Risk?

From the Authors:

We thank the author for their thoughtful and detailed letter in response to our recent study on the use of vascular endothelial growth factor (VEGF) supplementation delivered through a nanodiamond-based system (ND-VEGF) for the treatment of congenital diaphragmatic hernia (CDH) (1). We greatly appreciate their recognition of the potential of this approach to address a long-standing clinical challenge in the management of CDH.

We fully agree that, although VEGF plays a critical role in promoting lung angiogenesis and development, which is particularly relevant in the hypoplastic lungs seen in CDH, its systemic administration raises valid safety concerns. Our study was motivated by the pressing need for more effective therapies that go beyond current interventions, such as fetal tracheal occlusion, which, although beneficial in some cases, can result in limited and often variable improvement in lung development. We aimed to explore VEGF not only as a therapeutic molecule but also as a biologically grounded strategy to restore a key signaling axis that is disrupted in both human CDH lungs and experimental models.

It is important to note that we believe our study provides several novel contributions to the field:

• 1.Human relevance: By identifying VEGF downregulation in human fetal CDH lungs and recapitulating these findings in a physiologically relevant ex vivo model, we confirmed that impaired VEGF signaling is a core feature of CDH pathology.
• 2.Restorative potential: Our findings demonstrate that exogenous VEGF supplementation restores branching morphogenesis and epithelial progenitor proliferation, two key deficits in CDH lungs, highlighting VEGF’s central role in lung development.
• 3.Therapeutic synergy: The use of ND-VEGF in vivo showed complementary effects to tracheal occlusion, suggesting that this therapy could work either alongside or as an alternative to existing mechanical interventions.
• 4.Nanoparticle-based precision delivery: The ND-VEGF platform represents a significant step forward in targeted fetal therapy, offering a strategy to concentrate biologically active agents within the lung while limiting systemic exposure.

We do not take lightly the concerns raised regarding the systemic risks of VEGF-based therapies, particularly during the vulnerable stages of prenatal development. Although our delivery system was designed with organ-specific targeting in mind, we acknowledge that further investigation is needed to fully characterize its biodistribution and potential effects on other developing organs. These considerations are not only valid but essential as we move toward potential clinical translation.

As the letter rightly suggests, comprehensive preclinical studies with long-term follow-up, including multiorgan analysis and functional assessments, will be critical to ensure the safety and sustainability of VEGF-based therapies. We also recognize the need for deeper exploration into the optimal dosing, timing, and duration of VEGF supplementation to maximize lung-specific benefits while minimizing systemic risks. We strongly support this approach and believe that our study lays the foundation for such work.

In closing, we are grateful for the opportunity to engage in this important dialogue and for the constructive critique offered. We share the authors’ vision of a future where treatments for CDH not only improve survival but also safeguard long-term developmental health. We hope that our work contributes meaningfully to that goal.