A novel tetrahedral framework nucleic acid‐derived chemodynamic therapy agent for effective glioblastoma treatment

Abstract Chemodynamic therapy (CDT) has garnered significant attention for treating diverse malignant tumours due to its minimally invasive nature, reduced damage to healthy tissues, and potential mitigation of side effects. However, its application in glioblastoma (GBM) is hindered by the diminished capacity of CDT agents to traverse the blood–brain barrier (BBB), inadequate tumour targeting efficiency, and restricted availability of H 2 O 2 within the tumour microenvironment (TME). To address these challenges, we devised a novel CDT agent (Fe@tFNAs‐ANG‐3AT) based on a tetrahedral framework nucleic acids (tFNAs). Fe@tFNAs‐ANG‐3AT was constructed by anchoring iron ions (Fe 3+ ) onto the dual appendages‐modified tFNAs. Specifically, one appendage, Angiopep‐2 (ANG, a penetrating peptide), facilitates Fe@tFNAs‐ANG‐3AT penetration across the BBB and selective targeting of tumour cells. Simultaneously, the second appendage, 3‐Amino‐1,2,4‐triazole (3AT, a H 2 O 2 enzyme inhibitor), augments the H 2 O 2 levels required for effective CDT treatment. Upon tumour cell internalization, the loaded Fe 3+ in Fe@tFNAs‐ANG‐3AT is reduced to Fe 2+ by the overexpressed glutathione (GSH) in the TME, catalysing the generation of cytotoxic hydroxyl radicals (·OH) and inducing tumour cell death via elevated oxidative stress levels within tumour cells. It is anticipated that Fe@tFNAs‐ANG‐3AT holds promise as a transformative treatment strategy for GBM.