Lipid nanoparticles containing polynucleotides encoding propionyl-coa carboxylase alpha and beta subunits and uses thereof

A lipid nanoparticle comprising a first messenger RNA (mRNA) comprising a first open reading frame (ORF) encoding a propionyl-CoA carboxylase alpha (PCCA) polypeptide and a second mRNA comprising a second ORF encoding a propionyl-CoA carboxylase beta (PCCB) polypeptide, wherein the lipid nanoparticle comprises a compound of Formula (II):

• or its N-oxide, or a salt or isomer thereof,
• wherein R′a is R′branched or R′cyclic;
• wherein
• R′branched is:
• and R′cyclic is:
• and
• R′b is:
• wherein
• denotes a point of attachment;
• Raγ and Raδ are each independently selected from the group consisting of H, C1-12 alkyl, and C2-12 alkenyl, wherein at least one of Raγ and Raδ is selected from the group consisting of C1-12 alkyl and C2-12 alkenyl;
• Rbγ and Rbδ are each independently selected from the group consisting of H, C1-12 alkyl, and C2-12 alkenyl, wherein at least one of Rbγ and Rbδ is selected from the group consisting of C1-12 alkyl and C2-12 alkenyl;
• R2 and R3 are each independently selected from the group consisting of C1-14 alkyl and
• C2-14 alkenyl;
• R4 is selected from the group consisting of —(CH2)nOH wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, and
• wherein
• denotes a point of attachment;
• wherein
• R10 is N(R)2;
• each R is independently selected from the group consisting of C1-6 alkyl, C2-3 alkenyl, and H;
• and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
• each R′ independently is a C1-12 alkyl or C2-12 alkenyl;
• Ya is a C3-6 carbocycle;
• R*″a is selected from the group consisting of C1-15 alkyl and C2-15 alkenyl;
• and
• s is 2 or 3;
• m is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9;
• l is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9.