A combination of physicochemical tropism and affinity moiety targeting of lipid nanoparticles enhances organ targeting

Two camps have emerged in the targeting of nanoparticles to specific organs and cell types: affinity moiety targeting, which conjugates nanoparticles to antibodies or similar molecules that bind to known surface markers on cells; and physicochemical tropism, which achieves specific organ uptake based on the nanoparticles physical or chemical features (e.g., binding to endogenous proteins). Because these camps are largely non-overlapping, the two targeting approaches have not been directly compared or combined. Here we do both, using intravenous (IV) lipid nanoparticles (LNPs) whose original design goal was targeting to the lungs endothelial cells. For an affinity moiety, we utilized PECAM antibodies, and for physicochemical tropism, we used cationic lipids, both having been heavily studied for lung targeting. Surprisingly, the two methods yield nearly identical levels of lung uptake. However, aPECAM LNPs display much greater specificity for endothelial cells. Intriguingly, LNPs that possess both targeting methods had >2-fold higher lung uptake than either method alone. The combined-targeting LNPs also achieved greater uptake in already inflamed lungs, and greater uptake in alveolar epithelial cells. To understand how the macro-scale route of delivery affects organ targeting, we compared IV injection vs. intra-arterial (IA) injection into the carotid artery. We found that IA combined-targeting LNPs achieve 35% of the injected dose per gram (%ID/g) in the brain, a level superior to any other reported targeting method. Thus, combining affinity moiety targeting and physicochemical tropism provides benefits that neither targeting method achieves alone. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=56 SRC="FIGDIR/small/568061v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@281d31org.highwire.dtl.DTLVardef@1948026org.highwire.dtl.DTLVardef@693f99org.highwire.dtl.DTLVardef@1ce74cb_HPS_FORMAT_FIGEXP M_FIG C_FIG