Systematic Targeting of GD2‐Positive Neuroblastoma Tumors With a Photooncolytic Phage Nanovector Platform

Disialoganglioside-GD2 is a key molecular target for Neuroblastoma (NB) immunotherapy based on the employment of GD2-targeting antibodies. However, about 50% of treated patients can experience tumor relapse due to limited immune-mediated cytotoxicity and poor antibody penetration into tumors. To address this problem, a tumor-penetrating photo-oncolytic phage nanovector platform is genetically and chemically developed that selectively targets GD2-expressing NB cells. The phage bioconjugates, functionalized with different photosensitizers, result in specific and selective oncolysis of GD2-positive NB cells upon light irradiation, without affecting GD2-negative ones. The photo-oncolytic phage vectors are shown to deeply penetrate into GD2-positive tumor spheroids in vitro, and to cross biological barriers in a zebrafish xenograft model, maintaining their ablation specificity upon irradiation. Finally, to overcome resistance from GD2 loss, often linked to poor prognosis, a CRISPRa strategy is introduced to reactivate GD2 expression in GD2-negative cells. The approach offers a minimally invasive and highly effective strategy, addressing unmet needs in NB therapy.