Rolling Circle Amplification-Engineered DNA Nanoplatform for Synergistic In Vitro Breast Cancer Treatment Via Dual-Aptamer Programmed Co-Delivery of MoS ₂ 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–MoS 2 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 MoS 2 -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.