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

Abstract

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 via 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). In vitro 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.