Researchers at Tokyo University of Science have unveiled a significant advancement in healthcare: Takumi-shaped DNA nanostructures forming hydrogels for sustained drug delivery.
Published in the Journal of Controlled Release (doi.org/10.1016/j.jconrel.2024.11.052), the study, led by Professor Makiya Nishikawa, addresses challenges in traditional drug delivery by minimizing complexity and adverse effects while enhancing biocompatibility.
Hydrogels, polymeric substances holding large water volumes within a 3D network, serve as effective drug carriers by encapsulating bioactive agents for prolonged release. The team used DNA for its customizable physicochemical properties. Traditional methods using DNA ligase face limitations like allergic reactions and complex administration. To overcome these issues, the team designed 'polypodna' [polypod-shaped DNA], a polypod-like nanostructure of oligodeoxynucleotides (ODNs) [short DNA sequences] with partially complementary sequences. These structures create hydrogels that reform at the injection site, avoiding DNA ligase. Prior models needed many ODNs, increasing costs and off-target effects. The researchers introduced a Takumi-shaped DNA unit, reducing ODNs to two, to optimize and miniaturize DNA nanostructures for hydrogel assembly, addressing stability and retention time.
The Takumi shape uses eight to eighteen nucleotide-long palindromic stems, attached to two cohesive components via a thymidine spacer [a section of DNA]. Experiments showed that ODNs with stem lengths of twelve nucleotides or longer were crucial for hydrogel formation. Cohesive parts exhibited optimal behavior at ten nucleotides in length, enhancing hybridization and thermal stability.
*In vivo* experiments with doxorubicin-intercalated (inserted between layers) DNA hydrogels in mice revealed retention exceeding 168 hours post-administration. This correlated with enhanced anti-tumor efficacy due to controlled drug release. Professor Nishikawa noted that the optimized DNA hydrogel using an ODN with a stem length of 12 nucleotides and a cohesive part of 10 nucleotides showed more sustained retention than hexapodna-based [six-legged DNA] hydrogels in mice. This highlights potential in targeted immune responses, positioning Takumi-shaped DNA hydrogels as effective antigen delivery systems.
Beyond oncology, the study paves the way for biomedical applications, leveraging DNA's biocompatibility and effectiveness. With minimal DNA unit assembly, the study addresses the demand for advanced delivery systems, reinforcing the potential of DNA-based hydrogels in therapeutic strategies.