Compositions for the delivery of payload molecules to airway epithelium

A nanoparticle comprising:

• (a) a lipid nanoparticle core comprising:
• (i) an ionizable lipid,
• (ii) a phospholipid,
• (iii) a structural lipid, and
• (iv) a PEG-lipid, and
• (b) a polynucleotide or polypeptide payload encapsulated within the core for delivery into a cell, and
• (c) a cationic agent.

A nanoparticle comprising:

• (a) a lipid nanoparticle core,
• (b) a polynucleotide or polypeptide payload encapsulated within the core for delivery into a cell, and
• (c) a cationic agent,
• wherein the nanoparticle exhibits a cellular accumulation of at least about 20% in epithelial cells and exhibits about 5% or greater expression in epithelial cells.

A nanoparticle comprising:

• (a) a lipid nanoparticle core,
• (b) a polynucleotide or polypeptide payload encapsulated within the core for delivery into a cell, and
• (c) a cationic agent,
• wherein the nanoparticle exhibits protein expression of about 0.5% to 50% in cells, wherein the cells are in vivo.

A process of preparing a nanoparticle comprising contacting a lipid nanoparticle with a cationic agent, wherein the lipid nanoparticle comprises:

• (a) a lipid nanoparticle core comprising:
• (i) an ionizable lipid,
• (ii) a phospholipid,
• (iii) a structural lipid, and
• (iv) a PEG-lipid, and
• (b) a polynucleotide or polypeptide payload encapsulated within the core for delivery into a cell.

A compound of Formula A2a:

• or a salt thereof, wherein:
• is a single or double bond
• R1 is C1-14 alkyl or C1-14 alkenyl;
• La is absent, —O—, —S—S—, —OC(═O), —C(═O)N—, —OC(═O)N—, CH2—NH—C(O)—, —C(O)O—, —OC(O)—CH2—CH2—C(═O)N—, —S—S—CH2, —SS—CH2—CH2—C(O)N—, or a group of formula (a):
• Y1 is C1-10 alkyl, 3 to 8-membered heterocycloalkyl, 5 to 6-membered heteroaryl, —C1-6 alkyl-(3 to 8-membered heterocycloalkyl), or —C1-6 alkyl-(5 to 6-membered heteroaryl),
• wherein the C1-10 alkyl, 3 to 8-membered heterocycloalkyl, 5 to 6-membered heteroaryl, —C1-6 alkyl-(3 to 8-membered heterocycloalkyl), and —C1-6 alkyl-(5 to 6-membered heteroaryl) comprises one to five primary, secondary, or tertiary amines or combination thereof;
• and wherein the C1-10 alkyl, 3 to 8-membered heterocycloalkyl, 5 to 6-membered heteroaryl, C1-6 alkyl-(3 to 8-membered heterocycloalkyl), and C1-6 alkyl-(5 to 6-membered heteroaryl) are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from C1-6 alkyl, halo, OH, —O(C1-6 alkyl), —C1-6 alkyl-OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, 3 to 8-membered heterocycloalkyl (optionally substituted with C1-14 alkyl comprising one to five primary, secondary, or tertiary amines or combination thereof), 5 to 6-membered heteroaryl, —NH-(3 to 8-membered heterocycloalkyl), and —NH(5 to 6-membered heteroaryl);
• and
• n is 1 or 2;
• with the proviso that the compound of Formula A2a is other than:

A compound of Formula A4:

• or a salt thereof, wherein:
• Z1 is OH or C3-6 alkyl;
• L is absent, —O—, —S—S—, —OC(═O), —C(═O)N—, —OC(═O)N—, —CH2—NH—C(═O)—, —C(═O)O—, —OC(═O)—CH2—CH2—C(═O)N—, —S—S—CH2, or —SS—CH2—CH2—C(O)N—;
• Y1 is C1-10 alkyl, 3 to 8-membered heterocycloalkyl, 5 to 6-membered heteroaryl, —C1-6 alkyl-(3 to 8 membered heterocycloalkyl), or —C1-6 alkyl-(5 to 6 membered heteroaryl),
• wherein the C1-10 alkyl, 3 to 8-membered heterocycloalkyl, 5 to 6-membered heteroaryl, —C1-6 alkyl-(3 to 8-membered heterocycloalkyl), and —C1-6 alkyl-(5 to 6-membered heteroaryl) comprises one to five primary, secondary, or tertiary amines or combination thereof;
• and wherein the C1-10 alkyl, 3 to 8-membered heterocycloalkyl, 5 to 6 membered heteroaryl, —C1-6 alkyl-(3 to 8-membered heterocycloalkyl), and —C1-6 alkyl-(5 to 6-membered heteroaryl) are each optionally substituted with 1, 2, 3, or 4 substituents selected from C1-6 alkyl, halo, OH, —O(C1-6 alkyl), —C1-6 alkyl-OH, NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, 3 to 8-membered heterocycloalkyl (optionally substituted with C1-14 alkyl comprising one to five primary, secondary, or tertiary amines or combination thereof), 5 to 6-membered heteroaryl, —NH(3 to 8-membered heterocycloalkyl), and —NH(5 to 6-membered heteroaryl);
• and
• n is 1 or 2.

A compound, or a salt thereof, selected from:

• Sterol
• amine no.
• Structure
• SA6
• SA7
• SA8
• SA12
• SA13
• SA14
• SA15
• SA16
• SA17
• SA18
• SA19
• SA20
• SA21
• SA24
• SA25
• SA26
• SA27
• SA28
• SA31
• SA32
• SA33
• SA34
• SA35
• SA36
• SA37
• SA38
• SA41
• SA42