Synthetic lipids for mRNA delivery

A method of treating a human lipoprotein metabolism disorder or a cardiovascular disease, comprising administering to a subject in need thereof a lipidoid nanoparticle comprising a lipid, a CRISPR/Cas9 mRNA, and a single guide RNA (sgRNA);

• wherein
• the sgRNA is single guide Angiopoietin-like 3 (sgANGPTL3) or single guide proprotein convertase subtilisin/kexin type 9 (sgPCSK9);
• the human lipoprotein metabolism disorder is associated with loss-of-function mutations in ANGPTL3 gene;
• the cardiovascular disease is associated with proprotein convertase subtilisin/kexin type 9 gene (PCSK9);
• and
• the lipid is represented by formula I:
• or a pharmaceutically acceptable salt thereof, wherein
• Z is
• and
• each RLipid is independently:
• wherein:
• each R1 is H or OH;
• each R2 is H;
• R3 and R4 are taken together to form an oxo (═O) group;
• X is CH2 O, or NH;
• m is an integer selected from 1-3;
• n is an integer selected from 1-14;
• p is 0 or 1;
• q is an integer selected from 1-10;
• and
• t is 0, 1, or 2.