Designing a Smart Multiple-Drug Delivery System for Combinatorial Therapeutics via DNA Nanotechnology

• Applicant: Yosub Ha, Ph.D.
• Subject Area: Biomaterials ; Medical Physics, Biomedical Technology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 574547697

This research project aims to develop a smart drug delivery system capable of executing combinatorial cancer therapies in a highly specific and programmable manner. Despite ongoing advances in cancer treatment, tumor heterogeneity remains a key challenge. Conventional chemotherapies often fail to eliminate all cancer cell populations, leading to treatment resistance and relapse. To address this, combinatorial therapeutic approaches have been introduced, which combine chemical drugs with physical therapies such as photothermal treatment. These approaches attempt to attack cancer cells through multiple mechanisms at once for greater therapeutic effect.However, current drug delivery platforms for such therapies face major limitations. First, many of them lack specificity for cancer cells and thus risk damaging healthy tissues. Second, they offer little control over the timing and location of drug release. Third, they typically cannot handle the sequential delivery of multiple drugs with different properties, which is necessary to effectively target diverse cancer cell types.This project addresses these limitations by designing a DNA-responsive multiple-drug delivery system that selectively activates only in cancer cells and releases therapeutic agents in a controlled, stepwise manner.The project is divided into two main parts.In the first part, a hydrogel system will be developed that contains several types of biopolymer-based nanoparticles. Each nanoparticle, stabilized by specially designed DNA strands, will carry a different therapeutic agent—three drugs and antibacterial silver nanoparticles. When the hydrogel is exposed to physiological salt concentrations (similar to those in the human body), a DNA-based cascade will be triggered, releasing the drugs in a preprogrammed sequence. This strategy allows precise temporal control over drug release.In the second part, a double-layer nanocarrier will be designed. The outer layer will contain a chemical drug, while the inner layer will hold a near-infrared (NIR) dye used for heat-based therapy. The system will be engineered to respond to specific microRNAs that are overexpressed in cancer cells. Upon entering such a cancer cell, the microRNA will initiate a DNA-strand displacement reaction, causing the outer layer to release its drug. This release will also trigger the inner layer to release the NIR dye. When irradiated with a laser, the dye produces heat, resulting in a dual attack on the cancer cell—first chemically, then physically.Overall, this project combines advanced biomaterials with DNA nanotechnology to create a next-generation cancer treatment platform. By enabling multi-drug loading, sequential release, and cancer-cell-specific activation, the proposed system offers a highly targeted and effective approach to cancer therapy with significant potential for clinical translation.

• DFG Programme: WBP Position