Rolling Circle Amplification-Engineered DNA Nanoplatform for Synergistic In Vitro Breast Cancer Treatment Via Dual-Aptamer Programmed Co-Delivery of MoS2 Quantum Dots and DOX

Achieving precise integration of molecular targeting, controlled drug release, and efficient photothermal conversion remains a critical challenge in the development of synergistic cancer nanotherapies. Here, we presented a programmable dual-aptamer DNA–MoS2 quantum dot (QDs) nanoplatform, constructed via multivariate hydrothermal synthesis and rolling circle amplification (RCA). Systematic optimization identified glutathione as the optimal sulfur source, resulting in the preparation of ultrasmall MoS2-QDs with strong 808 nm absorption, high colloidal stability, and excitation-dependent fluorescence. Covalent conjugation of these QDs to an RCA-derived DNA scaffold enabled high-density assembly of MUC1 and AS1411 aptamers and facilitated efficient doxorubicin (DOX) intercalation within GC-rich duplex regions. The resulting nanoplatforms demonstrated selective uptake by MCF-7 breast cancer cells, negligible internalization in normal fibroblasts, and DNase-responsive drug release. Upon near-infrared irradiation, the dual-aptamer assemblies elicited rapid photothermal heating, elevated intracellular reactive oxygen species (ROS), and mitochondrial dysfunction, generating a potent synergistic chemo-photothermal cytotoxicity. DOX-loaded RA@QDs further inhibited cancer cell migration, highlighting the enhanced therapeutic efficacy. This modular nanoplatform integrates the programmable DNA architecture, precise molecular targeting, enzyme-responsive drug delivery, and efficient photothermal activation, providing a scalable and mechanistically unified strategy for precision cancer nanomedicine.