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Targeted Gold Nanoclusters for Synergistic High-Risk Neuroblastoma Therapy through Noncanonical Ferroptosis
Liyuan Xue1, Kaidi Luo1, Kaixiao Hou1
1Department of Chemistry, College of Chemistry and Life Science, Center of Excellence for Environmental Safety and Biological Effects, Beijing University of Technology, Beijing 100124, China.
Abstract:
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.
Insights
Gold nanoclusters target high-risk neuroblastoma (NB), enhancing ferroptosis by boosting iron metabolism. This novel approach overcomes drug resistance and shows promise for safer NB treatment in children.
Area of Science:
- Biomedical Engineering
- Oncology
- Nanotechnology
Background:
- High-risk neuroblastoma (NB) in children has a poor prognosis due to resistance to apoptosis.
- Current ferroptosis-inducing therapies for NB face challenges with drug resistance and side effects.
Purpose of the Study:
- To investigate the potential of gold nanoclusters to overcome ferroptosis resistance in high-risk neuroblastoma.
- To develop a targeted nanodrug delivery system for enhanced ferroptosis induction in NB.
Main Methods:
- Development of a gold nanocluster conjugated with an NB-targeting peptide (NANT).
- Assessment of NANT's effect on iron metabolism and ferroptosis induction in NB cells.
- Evaluation of NANT's efficacy in tumor spheroid and xenograft models.
Main Results:
- NANT significantly affects iron metabolism, sensitizing high-risk NB cells to ferroptosis.
- NANT promotes ferroptosis via a noncanonical pathway involving heme oxygenase-1 and Fe(II) accumulation.
- NANT effectively inhibits NB tumor growth in preclinical models with demonstrated cardiosafety.
Conclusions:
- NANT represents a promising strategy to overcome ferroptosis resistance in high-risk neuroblastoma.
- The targeted delivery and noncanonical ferroptosis induction by NANT offer a safer treatment option for pediatric NB.
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