Precision gene editing in infant neuroblastoma: a review of nanoparticle: enabled CRISPR/Cas9 therapies

Abstract

Infant neuroblastoma (NB), defined by diagnosis during the first year of life, represents a clinically heterogeneous disease spectrum ranging from localized tumours with favourable outcomes and a capacity for spontaneous regression, to high-risk metastatic disease requiring intensive multimodal therapy. In infants, treatment intensity is determined by disease stage, tumor biology, MYCN status, risk classification, symptoms, response to therapy, and metastatic involvement, particularly relevant to high-risk disease, consequently the potential toxicity of intensive treatment is specific to high-risk disease, as compared to favorable risk tumors which can be managed with surgery, reduced frequency techniques, or observations. Important determinations of neuroblastoma biology and prognosis are genetic alterations involving MYCN and ALK, but the predominately investigated field with therapeutic feasibility of targeting these changes with CRISPR/Cas9 is in preclinical neuroblastoma models rather than in infants. An investigational hypothesis is accordingly considered by their potential relevance to infant neuroblastoma rather than an established clinical application. The safe and efficient in vivo delivery of CRISPR/Cas9 components remains a major challenge, owing to cargo size, immunogenicity, and degradation, particularly within the delicate physiological environment of infants. This review emphasises the need for advanced delivery systems, focusing on the potential of nanoparticle-mediated approaches. Emerging preclinical findings support the feasibility of nanoparticle-mediated CRISPR/Cas9 delivery, although direct evidence in infant neuroblastoma remains limited. Importantly, the evidence for nanoparticle-mediated CRISPR/Cas9 therapy remains largely preclinical. Studies performed in general neuroblastoma models, non-cancer models, or adult cancers should not be interpreted as direct evidence of efficacy in infant neuroblastoma.