Novel lipid nanoparticle formulations for delivery of nucleic acids

A lipid nanoparticle comprising:

• about 45 mol % to about 65 mol % of an ionizable lipid, preferably an ionizable lipid according to formula (II)
• or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein
• Ra is selected from:
• Rb is selected from:
• A is —S—;
• R1 is an ethanediyl or linear or unbranched alkanediyl having 2 to 3 carbon atoms;
• R2 is an alkanediyl having 2 to 8 carbon atoms;
• R3 is optional, and if present, is —R5—C(O)—O—, —R5—O—C(O)—, —R5—C(O)—NH—, —R5—OC(O)—NH— or R5—NH—C(O)O—;
• R4 is a lipophilic substituent with 12 to 36 carbon atoms, wherein the lipophilic substituent with 12 to 36 carbon atoms is derived from tocopherol or tocotreinol;
• R5 is an alkanediyl having 1 to 6 carbon atoms;
• X is a carbon atom bonded to a hydrogen atom (CH) or a nitrogen atom, preferably a carbon atom bonded to a hydrogen atom (CH);
• about 4 mol % to about 15 mol %, preferably about 4 mol % to about 9 mol % of a phospholipid, preferably a phospholipid selected from DSPC and DPhyPE, more preferably wherein the phospholipid is DPhyPE;
• about 1 mol % to about 6 mol %, preferably about 2.5 mol % to about 5 mol %, more preferably about 2.5 mol % of a phosphatidylserine, preferably DPhyPS;
• about 25 mol % to about 45 mol % of a sterol, preferably cholesterol;
• less than about 1.5 mol %, preferably about 1 mol % of a polymer conjugated lipid, preferably of a PMOZ-lipid, more preferably a PMOZ-lipid not comprising a sulphur group (—S—);
• and
• one or more nucleic acid, preferably an mRNA.