Post by Vesiculab

Improving targeted mRNA delivery with integrin αVβ3-binding lipid nanoparticles: in their latest work, Sebastian Bayer, María García-García, Raffaele Senatore, Christoph Rademacher at University of Vienna and collaborators performed fragment screening under RGD saturation to identify selective ligands for integrin αVβ3, a marker upregulated on tumor endothelial cells. Because poor perfusion and abnormal vasculature limited direct drug delivery to solid tumors, targeting neighboring endothelial cells represented a promising alternative. Although orthosteric RGD ligands achieved high affinity, they suffered from cross-reactivity. The authors therefore explored low-affinity, non-orthosteric ligands displayed multivalently on nanoparticles to exploit avidity and improve αVβ3 selectivity. 🔗 https://lnkd.in/exXGARTy Structure–activity relationship analysis identified a 4-methylpyrimidine-2-amine binding motif and a conjugation-tolerant position for linker attachment. Displaying the lead compound on liposomes and lipid nanoparticles produced time-, dose-, and valency-dependent uptake in αVβ3-expressing model cells and primary human umbilical vein endothelial cells. Unlike RGD-decorated nanoparticles, fragment-targeted nanoparticles showed superselective behavior, with a sharp valency-dependent uptake threshold in αVβ3-overexpressing cells. Importantly, targeted LNPs delivered mRNA that produced six-fold higher functional protein expression than controls. Overall, their study introduced non-orthosteric small-molecule ligands for αVβ3 and demonstrated their use in a multivalent, superselective delivery platform. An article co-authored by Maria Stratoudaki, Alina Markhof, Angelika Berger-Becvar and Anna Sofia Parianou. #LNPs #mRNA #targeteddeliverey #Vesiculab