Artificial amino acid containing lipo-oligomers for ribonucleoprotein delivery

A nanoparticle for siRNA or phosphorodiamidate morpholino oligomers (PMO) delivery comprising one or more siRNA(s) or PMO(s) as cargo;

• and a carrier comprising a sequence-defined T-shape lipo-oligomer, comprising an artificial amino acid, wherein the artificial amino acid is an oligo(alkylamino) acid, and
• wherein the T-shape lipo-oligomer comprises the sequence of formula I:
• wherein
• Kc is a central lysine;
• Kf is a further lysine linked to the ε-amino group of Kc;
• FA is a fatty acid covalently linked to the ε- and α-amino group of Kf;
• C is cysteine and n=0 or 1, preferably n=0
• Y3 is a tyrosine tripeptide;
• H is histidine and n(outer) and n(inner) are independently selected from 0, 1 or 2;
• and
• X1 is an oligo(alkylamino) acid of formula IIIa:
• wherein n=2 or 3, alternating 2 and 3 or alternating 3 and 2;
• and m=3 or 4;
• and
• wherein R is
• —(CH2)y—CO2H, wherein y=2, 3 or 4;
• wherein z=0 or 1,
• preferably
• more preferably
• —CH2—CH(c-hexyl)-CH2—CO2H;
• or
• —CH2—NRa—CH2—CO2H, wherein Ra═H, CH2—CF3, and
• wherein the two fatty acids are saturated or unsaturated C12 to C22 fatty acids, preferably the two fatty acids are selected from the group consisting of oleic acid (OleA), linoleic acid (LinA), linolenic acid (LenA) or hydroxy steric acid (OHSteA), preferably OleA, LinA or OHSteA, more preferably LinA or OHSteA.

A conjugate comprising a phosphorodiamidate morpholino oligomer (PMO) covalently linked to a carrier comprising a sequence-defined T-shape lipo-oligomer, comprising an artificial amino acid, wherein the artificial amino acid is an oligo(alkylamino) acid, and

• wherein the T-shape lipo-oligomer comprises the sequence of formula I:
• wherein
• Kc is a central lysine;
• Kf is a further lysine linked to the ε-amino group of Kc;
• FA is a fatty acid covalently linked to the ε- and α-amino group of Kf;
• C is cysteine and n=0 or 1, preferably n=0
• Y3 is a tyrosine tripeptide;
• H is histidine and n(outer) and n(inner) are independently selected from 0, 1 or 2;
• and
• X1 is an oligo(alkylamino) acid of formula IIIa:
• wherein n=2 or 3, alternating 2 and 3 or alternating 3 and 2;
• and m=3 or 4;
• and
• wherein R is
• —(CH2)y—CO2H, wherein y=2, 3 or 4;
• wherein z=0 or 1,
• preferably
• more preferably
• —CH2—CH(c-hexyl)-CH2—CO2H;
• or
• —CH2—NRa—CH2—CO2H, wherein Ra═H, CH2—CF3, and
• wherein the two fatty acids are saturated or unsaturated C12 to C22 fatty acids, preferably the two fatty acids are selected from the group consisting of oleic acid (OleA), linoleic acid (LinA), linolenic acid (LenA) or hydroxy steric acid (OHSteA), preferably OleA, LinA or OHSteA, more preferably LinA or OHSteA.