The present invention provides, in part, phenolic acid lipid compounds of Formula (I), and sub-formulas thereof, or a pharmaceutically acceptable salt thereof. The compounds provided herein can be useful for delivery and expression of mRNA and encoded protein, e.g., as a component of liposomal delivery vehicle, and accordingly canbe useful for treating various diseases, disorders and conditions, such as those associated with deficiency of one or more proteins.

##STR00001##

Disclosed is a novel composition of lipid nanoparticles for stabilizing a nucleic acid drug and enhancing delivery in vivo. Lipid nanoparticles include a nucleic acid drug and a lipid, and the nucleic acid includes all of mRNA-based vaccines, RNA for immune boosters, miRNA, siRNA, pDNA, antisense ODN, and pDNA. The lipid of nanoparticles includes a trehalose-based lipid, an ionizable lipid, a phospholipid, a PEG-lipid, and a structure-maintaining lipid. The structure-maintaining lipid provides a composition that can replace commonly used cholesterol with a lithocholic acid derivative, a glycyrrhetinic acid derivative, or a diosgenin derivative. The lipid nanoparticles can be used as a vaccine or therapeutic agent, depending on the type of nucleic acid drug that is used.

The invention provides lipid nanoparticle-based compositions with improved properties for delivery of biologically active agents, engineered cells, and methods for delivery of the agents.

A lipid membrane structure includes, as lipid components, a lipid compound represented by Formula (I):

##STR00001##

[in the formula, a represents an integer of 3 to 5; b represents an integer of 0 or 1; R.sup.1 and R.sup.2 each independently represents a linear hydrocarbon group that may have —CO—O—; and X represents a 5- to 7-membered non-aromatic heterocyclic group or a group represented by Formula (B) (in the formula, d represents an integer of 0 to 3, and R.sup.3 and R.sup.4 each independently represents a C.sub.1-4 alkyl group or a C.sub.2-4 alkenyl group, where, R.sup.3 and R.sup.4 may be bonded to each other to form a 5- to 7-membered non-aromatic heterocycle (where, one or two C.sub.1-4 alkyl groups or C.sub.2-4 alkenyl groups may be substituted on the ring)].

Disclosed herein are lipid nanoparticles comprising a lipid phase and at least one lipophilic anti-inflammatory agent, and pharmaceutical compositions comprising lipid nanoparticles and methods for using lipid nanoparticles.

The invention pertains to a lipid-based microbubble stably binding a plurality of nucleic acids, and a method of delivering the microbubble and nucleic acids to a specific target site using ultrasound. The delivered nucleic acids create transgenic cells (i.e., for example, a transgenic tumor cell), wherein the transgenic cell expresses the proteins encoded by the delivered nucleic acids. This technology provides a significant improvement for microbubble-drug delivery platforms as known microbubble do not efficiently bind nucleic acids. The improvements described herein include but are not limited to identifying proper lipid proportionality ratios and/or cationic surfactant layers that provide an optimum mechanical index compatible with ultrasonics. Microbubble perfusion and/or nucleic acid delivery may be performed by a combination of imaging and ultrasound/microbubble targeted delivery to simultaneously perform low power two-dimensional imaging and high power microbubble destruction. Such systems are useful in therapeutics and/or diagnostics. For example, the data disclosed herein shows proof of principle in conjunction with the delivery of therapeutic siRNA molecules to slow tumor growth.

The present invention provides a cationic lipid, which allow nucleic acids to be easily introduced into cells, represented by formula (I) (wherein: R.sup.1 and R.sup.2 are, the same or different, alkenyl, etc, and X.sup.1 and X.sup.3 are hydrogen atoms, or are combined together to form a single bond or alkylene, and X.sup.3 is absent or is alkyl, etc, Y is absent or anion, a and b are, the same or different, 0 to 3, and L.sup.3 is a single bond, etc, R.sup.3 is alkyl, etc, L.sup.1 and L.sup.2 are —O—, —CO—O— or —O—CO—), a composition comprising the cationic lipid and a nucleic acid, and a method for introducing a nucleic acid into a cell by using the composition comprising the cationic lipid and the nucleic acid, and the like. ##STR00001##

The present invention provides, among other things, methods and compositions for treating primary ciliary dyskinesia (PCD) based on mRNA therapy. The compositions used in treatment of PCD comprise an mRNA comprising a dynein axonemal intermediate chain 1 (DNAI1) coding sequence and are administered at an effective dose and an administration interval such that at least one symptom or feature of PCD is reduced in intensity, severity, or frequency or has a delayed onset. mRNAs with optimized DNAI1 coding sequences are provided that can be administered without the need for modifying the nucleotides of the mRNA to achieve sustained in vivo function.

The disclosure features novel lipids and compositions involving the same. Nanoparticle compositions include a novel lipid as well as additional lipids such as phospholipids, structural lipids, and PEG lipids. Nanoparticle compositions further including therapeutic and/or prophylactics such as RNA are useful in the delivery of therapeutic and/or prophylactics to mammalian cells or organs to, for example, regulate polypeptide, protein, or gene expression.

Described herein are compositions and methods for reducing off-target deposition of therapeutic and/or imaging agents in a subject with cancer comprising administering to the subject a predose of an interferon composition and/or a nucleic acid and a nanoparticle mimic, e.g., a lipoplex composition or a virus-like particle, such that epithelial tightening occurs in nontumor tissue of the subject thereby reducing uptake or accumulation of the therapeutic and/or imaging agent in off-target, nontumor tissue compared to tumor tissue.