Targeted Gold Nanoclusters for Synergistic High-Risk Neuroblastoma Therapy through Noncanonical Ferroptosis

Children with extracranial high-risk neuroblastoma (NB) have a poor prognosis due to resistance against apoptosis. Recently, ferroptosis, another form of programmed cell death, has been tested in clinical trials for high-risk NB; however, drug resistance and side effects have also been observed. Here, we find that the gold element in gold nanoclusters can significantly affect iron metabolism and sensitize high-risk NB cells to ferroptosis. Accordingly, we developed a gold nanocluster conjugated with a modified NB-targeting peptide. This gold nanocluster, namely, NANT, shows excellent NB targeting efficiency and dramatically promotes ferroptosis. Surprisingly, this effect is exerted by elevating the noncanonical ferroptosis pathway, which is dependent on heme oxygenase-1-regulated Fe(II) accumulation. Furthermore, NANT dramatically inhibits the growth of high-risk NB in both tumor spheroid and xenograft models by promoting noncanonical ferroptosis evidenced by enhanced intratumoral Fe(II) and heme oxygenase-1. Importantly, this strategy shows excellent cardiosafety, offering a promising strategy to overcome ferroptosis resistance for the efficient and safe treatment of children with high-risk neuroblastoma.