JAG1-siRNA-Lipid Nanoparticles Suppress Infantile Hemangioma Angiogenesis

Background: Infantile hemangioma (IH) is the most common benign vascular tumor of infancy, and propranolol, the current first-line treatment, requires prolonged twice-daily dosing and has adverse systemic effects. Methods: Using the public GSE127487 transcriptomic dataset together with weighted gene coexpression network analysis and protein–protein interaction network analysis, we identified JAG1, a principal endothelial Notch ligand, as the most connected node in the disease protein–protein interaction network, with elevated expression across all clinical stages of IH. To test its use as a drug target, we engineered a lipid nanoparticle (LNP) composed of SM-102/DSPC/cholesterol/DMG-PEG2000 that carried JAG1-specific siRNA. Results: At an N/P ratio of 8, the formulation efficiently encapsulated the siRNA, protected it from serum nucleases, and remained colloidally stable. LNP-mediated JAG1 knockdown reduced Matrigel network formation by hemangioma stem cells in vitro. In a hemangioma xenograft model, the intratumoral delivery of JAG1 siRNA reduced tumor volume by approximately 75%, tumor weight by approximately 80%, and microvessel density by more than half, without overt toxicity to the measures collected (body weight and clinical observation). Conclusions: In this preclinical model, JAG1 emerges as a credible therapeutic target, and LNP-delivered JAG1 siRNA is a promising gene-silencing strategy against IH angiogenesis.