In a paper published in Nature Nanotechnology in April 2020 (Q. Cheng et al. Nat. Nanotechnol. 15, 313–320; 2020) the authors addressed this limitation and proposed an approach dubbed SORT, a short for Selective ORgan Targeting, to extend LPNs targeting to organs other than liver. Daniel Siegwart, corresponding author of the paper from the University of Texas Southwestern Medical Center in Dallas, USA, recounts: “We started this project because we wanted to understand the mechanisms that drove liver tropism and then made specific changes designed to avoid liver delivery”. Key observations came when investigating the physico–chemical characteristics of liver-targeting LPNs: they noticed that their apparent global pKa was always between 6.2 and 6.5, and were highly enriched in Apolipoprotein E, just like very-low-density lipoprotein found in nature.
LPNs are traditionally made of four components: ionizable cationic lipids, zwitterionic phospholipids, cholesterol and PEG lipids (Fig. 1). To control and tune their physico-chemical properties, Cheng et al. included a fifth component in their formulation, such as a quaternary lipid DOTAP (red SORT lipid in the figure). LPNs containing increasing percentages of DOTAP displayed altered biodistribution profiles, with 50% DOTAP delivering mRNA preferably to the lungs. Notably, Cheng et al. proceeded directly to carry out animal experiments bypassing cell culture experiments, in this way deviating from the conventional dogma of nanoparticle design for biomedical applications. This bold move was rendered necessary because cell cultures do not recapitulate the complexity of living models, as the plasma components that contribute to the protein corona are absent.
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