DNA-templated nanosheets for enhanced chemodynamic therapy and gene therapy to inhibit tumor recurrence and metastasis

Recurrence and metastasis stand as the primary contributors to mortality among patients with triple-negative breast cancer post-surgery, presenting a formidable clinical obstacle. Chemodynamic therapy (CDT), leveraging metal-ion-mediated Fenton-like reactions within the tumor microenvironment (TME), emerges as a promising avenue for addressing cancer metastasis. Despite recent progress, challenges such as tumor cell antioxidant defenses and epithelial-mesenchymal transition (EMT) impede the efficacy of CDT. Here, we introduce a novel approach using DNA-templated nanosheets (Dz-MnO₂) that combine the functions of Mn²⁺-mediated CDT and DNAzyme-mediated gene therapy to suppress tumor growth and metastasis. The Dz-MnO₂ nanosheets respond effectively to the TME, releasing Mn²⁺ and DNAzyme. The DNAzyme exhibits mRNA cleavage activity, specifically targeting oncogenic transcripts to reduce tumor progression. Mn²⁺ not only facilitates a Fenton-like reaction, enhancing the chemodynamic treatment effect, but also serves as a cofactor for DNAzyme, improving its catalytic efficiency. Concurrently, the nanosheets robustly silence the Twist1 gene, mitigating the EMT process and reinforcing CDT efficacy by suppressing apoptosis resistance. Results indicate that Dz-MnO₂ nanosheets efficiently polarize M2-tumor-associated macrophages (TAMs) into M1-TAMs by locally mitigating tumor hypoxia via catalyzing the decomposition of H₂O₂ into O₂. This collaborative strategy presents a promising approach to enhance CDT, effectively inhibiting tumor recurrence and metastasis.