Crab-shaped DNA tetrahedral nanomachine for silencing undruggable mRNA targets in prostate cancer

Cancer-associated gene fusions and mutations have emerged as a promising wellspring of therapeutic neoantigens. However, the lack of a precise and expeditious drug design pipeline has unfortunately missed the opportunity for timely treatment. Due to the intricate and arbitrary nature of these mutations and fusions, navigating the intricate terrain of 3D protein structures presents additional challenges. Despite significant advancements in targeted therapy, there are still a significant number of targets that cannot be effectively targeted, hindering further therapeutic efficacy. Moreover, the conditional efficacy of RNA interference through siRNA is compromised by the off-target phenomena, leading to associated toxic side effects. To address these limitations, we have developed a meticulously engineered DNA nanostructure in the form of a captivating crab-shaped DNA tetrahedron. This design not only ensures efficient interference with mRNA, but also facilitates ease and rapidity in synthesis. Additionally, it demonstrates an unprecedented ability to suppress the expression of previously considered "undruggable", which are crucial in targeted therapies. Through in vivo experimentation within a murine prostate cancer model, the DNA nanostructure has shown significant effectiveness in overcoming drug resistance, thus clearly displaying its substantial potential for clinical translation applications.