MicroRNA-Responsive Nanoplatform with Dynamic Size Switching for Enhanced Tumor Penetration and Synergistic Photothermal/Photodynamic Therapy

Cancer phototherapies, such as photodynamic therapy (PDT) and photothermal therapy (PTT), are often limited by poor tumor accumulation, insufficient penetration, and lack of real-time adaptability to the tumor microenvironment. To address these challenges, we developed an intelligent nanoscale theranostic nanoplatform, TDN HM -Au@IR780, based on a DNA tetrahedron (TDN) functionalized with gold nanoparticles (AuNPs) and the near-infrared dye IR780. The platform is further equipped with MUC1-targeting aptamers and catalytic hairpin assembly (CHA) circuits responsive to the tumor biomarker miRNA-21. Upon encountering miRNA-21 in the tumor microenvironment, the nanoparticles undergo in situ aggregation via CHA, dynamically switching from small, penetrative particles to larger aggregates that enhance retention. Under 808 nm laser irradiation, the aggregated system exhibits strong plasmonic coupling, achieving a high photothermal conversion efficiency of 45.8% and significantly amplified singlet oxygen generation. In vitro and in vivo studies using 4T1 breast cancer models demonstrate effective tumor-targeted accumulation, excellent biocompatibility, and potent synergistic photothermal/photodynamic effects. This nanoscale, dynamically responsive strategy is particularly well-suited for image-guided precision phototherapy of breast cancer, offering a promising avenue for nanomedicine-based oncology.