Human neuroblastoma (NB), a pediatric tumor inclined to relapse, after an initial response to therapy, usually develops resistance. Since several chemotherapeutics, including the weel known etoposide (ETO), eexert anticancer effect by increasing reactive oxygen species (ROS), NB cells overproduce antioxidant compounds becoming drugs-resistant. Moreover, ETO, although widely used, suffers from fast metabolism, poor solubility and systemic toxicity, that limit its administration dosage and its therapeutic efficiency. An appealing A strategy to sensitize NB cells to chemotherapy involves the use of less toxic natural compounds able to reducereducing their antioxidant defenses of NB cells and to induceand inducing ROS overproduction. In this contestConcerning this, although affected by several issues as instability and poor absorbabilitythat limit their clinical application, antioxidant/pro-oxidant polyphenols, such as gallic acid (GA), showed pro-oxidant anti-cancer effects and low toxicity for healthy cells, in several kind of tumors, not including NB. Herein, for the first time, free GA, two GA-dendrimers, and the dendrimer adopted as GA reservoir were tested on both sensitive and chemoresistant NB cells. Furthermore, the The dendrimer adopted as carrier for GA was exploited also for entrapping and protecting ETO and for enhancing its solubility and effectiveness.The dendrimer devicedevice, administered at the dose previously found active versus sensitive NB cells, induced ROS-mediated death both in sensitive NB cells and also in chemoresistant onecells. Free GA proved a dose-dependent ROS-mediated cytotoxicity on both cell populations. Intriguingly, when administered in dendrimer formulations at a dose not cytotoxic for NB cells, GA nullified any pro-oxidant activity of dendrimer. Unfortunately, due to GA, nanoformulations were inactive on NB cells, but GA resized in nanoparticles showed considerable ability in counteracting, at low dose, ROS production and oxidative stress, herein induced by the dendrimer. Interestingly, the ETO-dendrimer showed a synergistic action, controlled released over time with a significantly improved drug bioactivity, representing a novel biodegradable and promising device for the delivery of ETO into NB cells.