FluoNeeD · Fluorinated Lipid Nanoparticles for Gene Delivery and Diagnostics

The formulation of drug nanocarriers has attracted increasing attention over the last decades. In particular, the possibility to combinetherapeutic and imaging functionalities in a single nanoplatform (theranostic) has been widely explored to advance therapeuticapproaches and promote the transition from conventional medicine to personalized medicine.Drug nanocarriers, holding the potential to produce a revolution in medicine, are lipid nanoparticles (LNPs) for gene delivery. Theyhave proven versatility and efficacy even though today it is still not possible to predict and control their cellular uptake and targeteddelivery. One of the main unmet challenges of LNP formulations is increasing their cellular uptake and gene release into the cytosol.Currently, it is possible to follow the fate of LNPs after administration only with the addition of labels (e.g., fluorophore) or specificribonucleic acid (RNA) sequence encoding for fluorescent protein. This results in the lack of possibility to follow the fate of LNPs onceadministered in vivo with a non-invasive imaging technique. Theranostic strategies to deliver RNA and simultaneous imaging oftarget organs is an important unmet goal.Recently, it has been demonstrated that fluorination of components in gene delivery vehicles strongly improved their cellular uptakeand, most importantly, their gene endosomal escape. The fluorination strategies investigated so far use either -CF3 groups or longlinear perfluoroalkyl chains, but a tailored design of the fluorinated group could also endow the nanocarrier with excellent imagingfunctions. In this context, FluoNeeD strategy is to tailor fluorination of LNPs in order to: (i) improve their therapeutic efficacy byenhancing LNP cellular uptake and promoting gene endosomal escape; (ii) render LNPs trackable in vivo by 19F-MRI and in vitro/ex vivo by Raman microscopy.