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PEGYLATED LIPIDS, IN WHICH POLYETHYLENE GLYCOL (PEG) STRANDS ARE Attached TO LIPID HEADS, HAVE Several Functions IN A NANOPARTICLE. POLYETHYLENE GLYCOL (PEG)-COATED NANOPHARMACEUTICALS CAN Cause Mild TO Severe HYPERSENSITIVITY REACTIONS (HSRS), WHICH CAN Occasionally BE Life THREATENING OR EVEN Lethal. LIPID NANOPARTICLES Usually Contain A HELPER LIPID TO Promote Cell BINDING, CHOLESTEROL TO FILL THE GAPS Between THE LIPIDS, AND A POLYETHYLENE GLYCOL (PEG) TO Reduce OPSONIZATION BY SERUM PROTEINS AND RETICULOENDOTHELIAL CLEARANCE. THE MOST Effective NANOPARTICLES Were Ones THAT THE Body MISTOOK AS Low-DENSITY LIPOPROTEIN (LDL) CHOLESTEROL-Commonly Called Bad CHOLESTEROL. PROTEINS THAT Recognize LDL CHOLESTEROL IN THE BLOOD Bound TO SOME OF ALNYLAM’S NANOPARTICLES AND CARRIED THEM TO LDL RECEPTORS ON LIVER CELLS, WHICH THEN Caused THE CELLS TO ENGULF THE NANOPARTICLES IN AN ENDOSOME. LIPID NANOPARTICLES ARE SPHERICAL VESICLES Made OF IONIZABLE LIPIDS, WHICH ARE POSITIVELY Charged AT Low PH (ENABLING RNA COMPLEXATION) AND NEUTRAL AT PHYSIOLOGICAL PH (Reducing Potential Toxic Effects, AS Compared WITH POSITIVELY Charged LIPIDS, Such AS LIPOSOMES). THE RELATIVE Amounts OF IONIZABLE LIPID, HELPER LIPID, CHOLESTEROL AND PEG Substantially Affect THE EFFICACY OF LIPID NANOPARTICLES, AND Need TO BE OPTIMIZED FOR A Given Application AND ADMINISTRATION ROUTE. LNPS Used IN THE COVID-19 VACCINES Contain JUST Four Ingredients: IONIZABLE LIPIDS WHOSE Positive Charges BIND TO THE NEGATIVELY Charged Backbone OF MRNA, PEGYLATED LIPIDS THAT Help STABILIZE THE PARTICLE, AND PHOSPHOLIPIDS AND CHOLESTEROL MOLECULES THAT Contribute TO THE PARTICLE’S Structure