Spermine-responsive supramolecular DNA nanogels loaded with dual drugs for potential combined cancer therapy

The construction of nano-drug carriers based on deoxyribonucleic acid (DNA) has demonstrated significant therapeutic potential. Similarly, supramolecular therapeutic systems utilizing host-guest interactions have emerged as promising in nanomedicine. Building upon these approaches, we designed a size-controllable, multi-responsive supramolecular DNA nanogel (SDN) based on host-guest recognition for dual-drug co-delivery in cancer combination therapy. The nanogel incorporates doxorubicin (DOX, a chemotherapeutic agent) and methylene blue (MB, a photosensitizer). The assembly of SDN is driven by cucurbit[8]uril (CB[8]), which selectively binds two MB molecules-one from each of two Y-shaped DNA building blocks-forming a 1 : 2 host-guest complex that crosslinks the structures into a nanogel network. Meanwhile, the double-stranded DNA scaffold efficiently encapsulates DOX <i>via</i> intercalation, enabling SDN@DOX to co-deliver both drugs in a precisely controlled ratio. Notably, MB's photodynamic activity is initially suppressed upon CB[8] binding. However, upon cellular uptake, SDN@DOX responds to overexpressed spermine or specific peptide sequences in the tumor microenvironment, triggering MB release and restoring its photodynamic function. Concurrently, DNase I-mediated DNA degradation liberates DOX, enabling synergistic chemo-photodynamic therapy (PDT). <i>In vitro</i> studies confirmed that SDN@DOX enhances reactive oxygen species (ROS) generation in cancer cells and achieves superior therapeutic efficacy through combined PDT and chemotherapy. This stimuli-responsive, dual-drug delivery system offers a potentially robust and controllable platform for precision cancer treatment.