Chaotropic delivery of fully anionic oligonucleotides

forthcoming

Developing effective membrane transporters is a key challenge for the delivery of nucleic acid-based drugs. Despite the exponential discovery of such biomolecules with therapeutic potential, the majority of them may need to be discarded from further development for being too hydrophilic to cross the lipid membrane. Future delivery technologies require the development of conceptually new approaches that can overcome the emerging limitations of current carriers and strategies. Recently, superchaotropic boron clusters have been validated to activate the transport of a broad range of hydrophilic cargos. The “anionic nature” of these clusters offers an alternative transport scenario. The clusters will not aggregate with hydrophilic anionic domains and, instead, will be repelled by anions. Therefore, they could be exploited to modify the structure of cargos without altering their solubility and function. The main goal of this action is the connection of superchaotropic boron clusters to hydrophilic biomolecules such as probes and nucleic acids to enable their autonomous membrane transport, while preventing self-aggregation and unspecific interactions with other biological surfaces. This will be achieved through an interdisciplinary approach that will simultaneously provide me with valuable training in chemistry, biology and biophysics, promoting my scientific independence. Short oligonucleotides will be designed to incorporate a variable number of modified nucleosides for future functionalization with boron clusters. Modified oligonucleotides, such as those bearing alkyne or azide functions, will be purchased from commercial sources and combined with cluster derivatives using click chemistry. These new chaotropic oligonucleotide hybrids will allow understanding and validating the application of self-delivering fully anionic nucleic acids with therapeutic potential.