Self-Assembly and Biological Properties of Highly Fluorinated Oligonucleotide Amphiphiles.

Nucleic acids, used as therapeutics to silence disease-related genes, offer significant advantages over smallmolecule drugs: they provide high specificity, the ability to target “undruggable” molecules, and adaptability to a widerange of disease phenotypes. However, their instability in biological media, as well their rapid clearance from theorganism limit their applicability, necessitating the use of nanocarriers to overcome these challenges. Among thesestrategies, spherical nucleic acids (SNA)—composed of a densely packed corona of oligonucleotides around ananoparticle—have emerged as a powerful tool, in particular when self-assembled from DNA amphiphiles. This non-covalent strategy however has caveats, especially when it comes to stability in complex biological media, where theseSNAs disassemble in contact to serum proteins. Here, we developed highly fluorinated DNA amphiphiles that readilyself-assemble into SNAs and have tunable stability profiles in biological media. They are made of branched fluorinatedmoieties with potentially improved biodegradability as compared to their linear counterparts. Depending on the numberof fluorophilic interactions, the self-assembled SNAs can have excellent serum stabilities—up to days—and readilydeliver nucleic acid therapeutics for gene silencing applications. These systems show great potential as promisingcandidates for nucleic acid-based therapies