Engineered Peptide Coassembly Enables Precision Delivery of As(III)-Peptide Complexes and Counteracts Inflammation-Dependent Therapeutic Resistance in High-Risk Neuroblastoma

High-risk neuroblastoma (HR-NB) remains a devastating pediatric malignancy characterized by MYCN amplification-induced apoptotic resistance to conventional chemotherapeutic interventions. While arsenic trioxide (As(III)) demonstrates therapeutic potential through ferroptosis induction, its clinical application is severely constrained by dose-limiting systemic toxicity and consequent inflammation-mediated COX2/PGE₂ pathway activation, which confers ferroptosis resistance. Here we engineer a tumor microenvironment-responsive peptide coassembly As(III) delivery system (TCADS) that concurrently addresses these therapeutic challenges. TCADS comprises two rationally designed self-assembling peptides incorporating As(III)-binding domains, tumor-selective targeting moieties (MMP9-responsive and Tenascin C-targeting motifs), and the COX2 antagonist naproxen (NPX). In comprehensive preclinical evaluations encompassing subcutaneous and orthotopic neuroblastoma models, TCADS exhibits exceptional biocompatibility with markedly attenuated systemic toxicity and achieves enhanced tumor-selective accumulation through sequential MMP9-triggered As(III) liberation and TNC-mediated engagement of both tumor cells and cancer-associated fibroblasts, outperforming free drug combinations (As(III)+NPX). This precision-targeted approach empowers TCADS to effectively disrupt the deleterious inflammation-ferroptosis resistance cycle, thereby successfully overcoming treatment resistance and suppressing tumor progression by 85.0% and 95.4% in subcutaneous and orthotopic tumor models, respectively. This integrated paradigm of precision-targeted delivery coupled with microenvironment modulation establishes a compelling therapeutic framework for chemoresistant HR-NB and potentially other MYCN-amplified malignancies.