Abstract: Provided herein is a lipid nanoparticle encapsulating nucleic acid and having at least 30 mol % neutral lipid, a sterol or derivative thereof and a targeting moiety anchored in a lipid layer thereof via a lipophilic moiety. Further provided are methods of using the lipid nanoparticles for targeted delivery in vivo. Such lipid nanoparticle may exhibit significantly improved delivery and targeting to extrahepatic tissues and/or organs.

Abstract: Provided herein is a lipid nanoparticle comprising an encapsulated oligonucleotide molecule, wherein the oligonucleotide molecule is single-stranded or double-stranded and has a length of between 5 and 500 nucleotides; and 20 to 70 mol % of a neutral lipid content relative to total lipid present in the lipid nanoparticle, an ionizable lipid; a sterol; and optionally a hydrophilic polymer-lipid conjugate.

Abstract: A method comprises detecting one or more agent objects in a space around an ego object using image data captured by a camera of the ego object; storing a hierarchical nodal graph comprising a goal layer comprising one or more goal nodes and a plurality of interaction layers of interaction nodes subsequent to the goal layer; adding an interaction node to an interaction layer of interaction nodes of the plurality of interaction layers; determining a trajectory score for each of a plurality of trajectories based on one or more node scores of one or more nodes corresponding to the trajectory within the hierarchical nodal graph; and selecting a trajectory of the plurality of trajectories for the ego object based on the trajectory score for the trajectory.

Abstract: The present disclosure provides a lipid nanoparticle for extrahepatic delivery of mRNA, the lipid nanoparticle comprising: (i) mRNA cargo; (ii) a phosphatidylcholine lipid content of from 30 mol % to 70 mol %; (iii) a ionizable, cationic lipid content of from 5 mol % to 50 mol %; (iv) a sterol selected from cholesterol or a derivative thereof; and (v) a hydrophilic polymer-lipid conjugate that is present at a lipid content of 0.5 mol % to 5 mol. Further provided is a lipid nanoparticle comprising encapsulated mRNA and 20 to 70 mol % of a phosphatidylcholine lipid, an ionizable lipid; and at least one of a sterol and a hydrophilic polymer-lipid conjugate, the lipid nanoparticle exhibiting at least a 10% increase in gene expression of the mRNA in vivo as measured in one or more extrahepatic organs or tissues. Further provided are methods of administration of such lipid nanoparticles.

Abstract: The present disclosure provides unshielded lipid nanoparticles and a process that enables the production of such unshielded lipid nanoparticles, thereby overcoming previous challenges of making particles without causing aggregation thereof. The lipid nanoparticles comprise a nucleic acid cargo molecule; a sterol or a derivative thereof present at a content of at least 12 mol %; a neutral lipid, such as a phospholipid having a choline head group present at a content of between 22 mol % and 65 mol %; and an ionizable cationic amino lipid present at a content of between 15 mol % and 45 mol %; wherein the lipid nanoparticle is non-sterically stabilized with a hydrophilic polymer-lipid conjugate, or otherwise unshielded and wherein each mol % content is relative to total lipid present in the lipid nanoparticle.

Abstract: The present disclosure provides unshielded lipid nanoparticles and a process that enables the production of such unshielded lipid nanoparticles, thereby overcoming previous challenges of making particles without causing aggregation thereof. The lipid nanoparticles comprise a nucleic acid cargo molecule; a sterol or a derivative thereof present at a content of at least 12 mol %; a neutral lipid, such as a phospholipid having a choline head group present at a content of between 22 mol % and 65 mol %; and an ionizable cationic amino lipid present at a content of between 15 mol % and 45 mol %; wherein the lipid nanoparticle is non-sterically stabilized with a hydrophilic polymer-lipid conjugate, or otherwise unshielded and wherein each mol % content is relative to total lipid present in the lipid nanoparticle.

Abstract: The present disclosure provides a lipid nanoparticle comprising: a nucleic acid cargo molecule; sterol or a derivative thereof present at elevated content; neutral lipid; an ionizable lipid; and a hydrophilic polymer-lipid conjugate present at a content between 0.5 and 3 mol %, wherein each mol % content is relative to total lipid present in the lipid nanoparticle.

Abstract: The present disclosure provides a method for producing one or more intermediates for the synthesis of one or more ionizable lipids, the method comprising: (i) producing a beta-ketoacid by reacting a cyclic ester, a terminal hydroxyester or a derivative thereof, a dicarboxylic acid half ester, or an acid chloride derivative of the dicarboxylic acid half ester, in a condensation reaction, thereby producing the beta-ketoacid or a beta-ketoester that is hydrolyzed to produce the beta-ketoacid; and (ii) decarboxylating the beta-ketoacid, thereby producing the one or more intermediates, wherein the one or more intermediates have a structure that may be defined by Formula A. Further provided is a method for producing ionizable lipid from the intermediate comprising adding an ionizable head group moiety to (a) a ketone group of one or more intermediates having the structure that may be defined by Formula A; or (b) a corresponding alcohol of the intermediate.

Abstract: The present disclosure provides unshielded lipid nanoparticles and a process that enables the production of such unshielded lipid nanoparticles, thereby overcoming previous challenges of making particles without causing aggregation thereof. The lipid nanoparticles comprise a nucleic acid cargo molecule; a sterol or a derivative thereof present at a content of at least 12 mol %; a neutral lipid, such as a phospholipid having a choline head group present at a content of between 22 mol % and 65 mol %; and an ionizable cationic amino lipid present at a content of between 15 mol % and 45 mol %; wherein the lipid nanoparticle is non-sterically stabilized with a hydrophilic polymer-lipid conjugate, or otherwise unshielded and wherein each mol % content is relative to total lipid present in the lipid nanoparticle.

Abstract: Provided is lipid and methods of making such lipid, the lipid having the structure of: each R is independently an alkyl of C12 to C16, each alkyl having 1 to 3 C?C double bonds, wherein at least one of the double bonds is of Z geometry; R? is an optional alkyl; W is O, NH or NR?, wherein R? is a C1 to C3 alkyl group, such as a methyl; X is either absent or present, and if present, X is O, NH, or the NR?; and Z is an alkylamino chain as defined by [—(CH2)m—NG1G2G3], wherein m is 1-5 and G1 and G2 are, independently, the C1 to C3 alkyl group, G3 is absent, a hydrogen or the C1 to C3 alkyl group.

Abstract: Provided is lipid and methods of making such lipid having the structure of Formula A: each R is an alkyl having a carbon backbone of C12 to C16 having 1 to 3 C?C double bonds, at least one having Z-geometry; R? is an optional alkyl of C2 to C24 having 0 to 3 C?C double bonds; each R, and the R? alkyl group if present, is optionally substituted at one or more positions with a C1 to C3 alkyl; W and X are O or S; Y is absent and C1 and C2 are bonded, or Y is present and is a metheno, etheno or ethyno bridge optionally substituted with an alkylamino chain [—(CH2)m—NG1G2G3], wherein m is 1-5 and G1, G2 are, independently, C1 to C3 alkyl, G3 is absent, hydrogen or C1 to C3 alkyl, or wherein NG1G2G3 is a heterocycle; and Z and Z? are H or alkylamino.

Abstract: Provided herein is a method for producing an ionizable lipid that comprises: (i) reacting fatty esters in a Claisen condensation reaction in the presence of a catalyst, the Claisen condensation employing a weak base and carried out at a temperature of between ?10 and 60 degrees Celsius to produce a ketoester; (ii) reacting the ketoester produced in step (i) under conditions to produce a ketone from the ketoester in one or more steps via a hydrolysis and decarboxylation of the ketoester; and (iii) preparing the ionizable lipid from the ketone thereof using one or more synthesis steps resulting in an addition of an ionizable head group moiety to (a) the ketone; or (b) an alcohol produced from an optional reduction of the ketone to produce the alcohol, thereby producing the ionizable lipid. The ionizable lipid produced in step (iii) may be formulated in a drug delivery vehicle.

Abstract: The present disclosure provides a lipid nanoparticle for extrahepatic delivery of mRNA, the lipid nanoparticle comprising: (i) mRNA cargo; (ii) a phosphatidylcholine lipid content of from 30 mol % to 70 mol %; (iii) a ionizable, cationic lipid content of from 5 mol % to 50 mol %; (iv) a sterol selected from cholesterol or a derivative thereof; and (v) a hydrophilic polymer-lipid conjugate that is present at a lipid content of 0.5 mol % to 5 mol. Further provided is a lipid nanoparticle comprising encapsulated mRNA and 20 to 70 mol % of a phosphatidylcholine lipid, an ionizable lipid; and at least one of a sterol and a hydrophilic polymer-lipid conjugate, the lipid nanoparticle exhibiting at least a 10% increase in gene expression of the mRNA in vivo as measured in one or more extrahepatic organs or tissues. Further provided are methods of administration of such lipid nanoparticles.

Abstract: The present disclosure provides a lipid nanoparticle comprising encapsulated DNA vector and 30 to 60 mol % of a neutral lipid selected from sphingomyelin and a phosphatidylcholine lipid, and at least one of a sterol and a hydrophilic polymer-lipid conjugate, the lipid nanoparticle comprising a core comprising an electron dense region and an aqueous portion surrounded at least partially by a lipid layer comprising a bilayer and the lipid nanoparticle exhibiting at least a 10% increase in gene expression in a disease site or the liver, spleen or bone marrow at any time point after 24 or 48 hours post-injection as compared to a lipid nanoparticle encapsulating DNA vector with an Onpattro-type formulation of ionizable lipid/DSPC/cholesterol/PEG-lipid at 50/10/38.5/1.5, mol:mol, wherein the gene expression is measured in an animal model by detection of green fluorescent protein (GFP) or luciferase. Further provided are methods of medical treatment and uses of such lipid nanoparticles.

Abstract: The present disclosure provides a lipid nanoparticle comprising: a nucleic acid cargo molecule; sterol or a derivative thereof present at elevated content; neutral lipid; an ionizable lipid; and a hydrophilic polymer-lipid conjugate present at a content between 0.5 and 3 mol %, wherein each mol % content is relative to total lipid present in the lipid nanoparticle.

Abstract: The present disclosure provides a lipid nanoparticle for extrahepatic delivery of mRNA, the lipid nanoparticle comprising: (i) mRNA cargo; (ii) a phosphatidylcholine lipid content of from mol % to 70 mol %; (iii) a ionizable, cationic lipid content of from 5 mol % to 50 mol %; (iv) a sterol selected from cholesterol or a derivative thereof; and (v) a hydrophilic polymer-lipid conjugate that is present at a lipid content of 0.5 mol % to 5 mol. Further provided is a lipid nanoparticle preparation comprising lipid nanoparticles having encapsulated mRNA and 20 to mol % of a phosphatidylcholine lipid, an ionizable lipid; and at least one of a sterol and a hydrophilic polymer-lipid conjugate, the lipid nanoparticles exhibiting at least a 10% increase in gene expression of the mRNA in vivo as measured in one or more extrahepatic organs or tissues. The lipid nanoparticles have an electron dense region and a nitrogen-to-phosphate charge ratio of between 4 and 15.

Abstract: The present disclosure provides a lipid nanoparticle comprising: a nucleic acid cargo molecule; sterol or a derivative thereof present at elevated content; neutral lipid; an ionizable lipid; and a hydrophilic polymer-lipid conjugate present at a content between 0.5 and 3 mol %, wherein each mol % content is relative to total lipid present in the lipid nanoparticle.

Abstract: The present disclosure provides a lipid nanoparticle for extrahepatic delivery of mRNA, the lipid nanoparticle comprising: (i) mRNA cargo; (ii) a phosphatidylcholine lipid content of from mol % to 70 mol %; (iii) a ionizable, cationic lipid content of from 5 mol % to 50 mol %; (iv) a sterol selected from cholesterol or a derivative thereof; and (v) a hydrophilic polymer-lipid conjugate that is present at a lipid content of 0.5 mol % to 5 mol. Further provided is a lipid nanoparticle preparation comprising lipid nanoparticles having encapsulated mRNA and 20 to mol % of a phosphatidylcholine lipid, an ionizable lipid; and at least one of a sterol and a hydrophilic polymer-lipid conjugate, the lipid nanoparticles exhibiting at least a 10% increase in gene expression of the mRNA in vivo as measured in one or more extrahepatic organs or tissues. The lipid nanoparticles have an electron dense region and a nitrogen-to-phosphate charge ratio of between 4 and 15.

Abstract: The present disclosure provides a lipid nanoparticle comprising: a nucleic acid cargo molecule; sterol or a derivative thereof present at elevated content; neutral lipid; an ionizable lipid; and a hydrophilic polymer-lipid conjugate present at a content between 0.5 and 3 mol %, wherein each mol % content is relative to total lipid present in the lipid nanoparticle.