Translational advances in nanoparticle-mediated gene delivery for pediatric brain tumors: A structured narrative review

Pediatric brain tumors comprise molecularly heterogeneous malignancies with distinct anatomical barriers, oncogenic alterations, and developmental safety requirements. Nanoparticle (NP)-mediated delivery can protect siRNA, miRNA, mRNA, and plasmid DNA from enzymatic degradation while supporting cellular internalization and intracellular release. Lipid, polymeric, gold, iron oxide, silver, zinc oxide, dendrimer, carbon dot, and biomimetic systems differ substantially in biodistribution, biodegradation, endosomal escape, gene regulatory activity, and tissue persistence. Pediatric evidence remains predominantly preclinical. Functional nucleic acid delivery has been demonstrated in models of medulloblastoma, ependymoma, atypical teratoid/rhabdoid tumor, and diffuse midline glioma (DMG). Principal outcomes include suppression of PLK1, SMO, APE1, and PPM1D, HSVtk- mediated suicide-gene activity, and miRNA-induced regulation of tumor-cell differentiation. However, several formulations rely on intracranial administration, focused ultrasound-mediated barrier modulation, or combined pharmacological treatment. These experimental conditions restrict direct comparison and complicate attribution of therapeutic activity. Clinical evidence is limited to isolated reports of pediatric SGT-53 treatment and early-phase RNA-lipid vaccine programs. However, no NP-delivered nucleic acid product has demonstrated efficacy in a prospective pediatric brain tumor cohort. Translation is constrained by blood-brain barrier (BBB) heterogeneity, tumor-specific vascular permeability, endosomal sequestration, systemic clearance, immunogenicity, carrier persistence, and developmental neurotoxicity. Artificial intelligence can accelerate formulation screening and multi-parameter optimization, although AI-selected NP have not achieved validated pediatric brain tumor delivery. Clinical advancement requires molecularly annotated orthotopic models, separate quantification of the carrier and intact nucleic acid, tumor-cell-specific target modulation, age-stratified pharmacokinetics, and risk-adapted long-term surveillance. This narrative review article establishes a framework for precise NP-mediated nucleic acid therapies for pediatric brain tumors.