Programmable Comodification of DNA Soccer Framework with Fluorocarbon and Aptamer for Efficient siRNA Delivery

Efficient cytosolic delivery of nucleic acid therapeutics
remains
a central challenge for DNA nanostructure-based biomedical applications.
Here, we report a programmable DNA origami delivery platformthe
DNA Soccer Framework (DSF)cofunctionalized with fluorocarbon
chains and sgc8 aptamers to enhance cellular uptake and promote endosomal
escape for effective siRNA delivery. Fluorocarbon moieties of tunable
lengths and densities were grafted onto DSF to facilitate lipid raft-mediated
endocytosis, which favors cytosolic entry by bypassing lysosomal degradation.
Concurrently, aptamer comodification enabled selective targeting of
cancer cells. Systematic optimization revealed that a surface modification
ratio of 3:1 (fluorocarbon to aptamer) among the 90 available sites
yielded synergistic improvements in internalization and cytosolic
release, significantly enhancing siRNA-mediated gene silencing. Upon
loading with siRNA targeting Bcl2L12, the optimized DSF variant induced
highest apoptosis in two cancer cell lines, while maintaining minimal
cytotoxicity. This work establishes a robust and tunable platform
for nucleic acid delivery, advancing the application of DNA nanotechnology
in gene therapy and precision medicine.