Rational Design of Aptamer-Guided Framework Nucleic Acid Delivery Platform for Cancer Radionuclide Theranostics

DNA aptamers are single-stranded DNA molecules with three-dimensional structures that enable high-affinity and specific binding to target molecules, offering significant potential for precision medicine. Recent advances in DNA nanotechnology have allowed the fabrication of aptamer-guided framework nucleic acid delivery platforms with controllable size and valence. While these platforms have improved tumor delivery in drug delivery, the effects of size and valence on delivery efficacy have not been well studied, particularly in the context of radionuclide-based molecular imaging and therapy. Herein, we fabricate a series of radionuclide-labeled anti-PTK7 aptamer-guided tetrahedron framework nucleic acid delivery platforms (Apt-tFNAs) with varying sizes and valencies. These Apt-tFNAs are well-characterized, and their cell-specific binding ability is demonstrated to be dependent on size and valence. Further in vivo study via dynamic positron emission tomography (PET) scanning reveals that smaller-sized tFNAs improve tumor uptake and reduce liver and kidney retention when valence remains constant. Finally, a single aptamer-modified tFNA with an edge length of 17 bp presents the best tumor delivery efficacy and effective therapeutic performance when combined with either chemotherapy or immunotherapy. This study elucidates how controllable size and valence influence delivery efficacy and introduces optimized Apt-tFNA constructs as promising agents for enhancing targeted therapeutic outcomes.