Engineer Lipid Nanoparticle Surface Hydrophobicity to Modulate Nano-Bio Interface and Enable Tissue-Selective mRNA Delivery

Introduction: Clinical LNPs predominately target the liver upon systemic administration, which significantly limited the general application of IVT-mRNA as a systemic therapy. Current approach to enhance the extra-hepatic delivery of mRNAs focuses on tuning the apparent pKa of LNPs, which does not always predict the organ selectivity. The lipophilicity of nanoparticles can affect their interactions with serum proteins such as ApoE, which mediates LNP’s in vivo targeting. Here, we hypothesize that the lipophilicity of LNPs, together with their apparent pKa, can direct the extra-hepatic delivery of mRNAs.