With the advent of nucleosome/nucleotide intercalating drugs, DNA-based nanocarriers have recently gained impetus. However, most of the newly proposed DNA nanosystems are rather complex, thereby having low scalability and translatability. In this study, we propose a simple DNA nanomatrix core encapsulated within a chitosan shell, which is expected to enhance the encapsulation efficiency of intercalating drugs. This has been demonstrated using proflavine hemisulfate (PfHS), a model intercalating agent that shows improved ROS generation, among other anticancerous properties. The release of the drug from the nanomatrix is triggered by providing a heat trigger using IR-792 perchlorate, a known NIR photothermal sensitizer. © 2023 American Chemical Society.