Abstract: Disclosed herein are novel methods and compositions for treatment of obesity and/or related cardio-metabolic disorders such as dyslipidemia, Type 2 diabetes mellitus, NASH, NAFLD, and/or MAFLD. In some embodiments, compositions may include a) a miRNA antagomir or agomir oligonucleotide therapeutic (ONT) agent capable of modulating lipid oxidation, mitochondrial activity, energy expenditure, fat accumulation, inflammation, and/or necrosis, and b) a targeting element facilitating cellular uptake and delivery of a miRNA ONT agent to targeted adipocytes and metabolic organs.

Abstract: Disclosed are novel methods and compositions to treat Ovarian Cancers and their tumor microenvironment. Compositions may include: a. One or several therapeutic agents (microRNA ONT(s)) that can modulate the growth and metastasis of Ovarian Cancer cells; b. a targeting element (e.g. folic acid, fatty acid or peptide) which binds to the Ovarian Cancer cell surface receptor FOLR1 and/or the adipocyte cell surface receptors FAT and/or FABP4; and/or c. a lipid nanoparticle carrier that enhances the intra-cellular penetration of the therapeutic agents while protecting them from degradation. The disclosure further relates to a method for targeted delivery to Ovarian Cancer cells and their tumor microenvironment of a therapeutic system to treat Ovarian Cancers in a subject in need thereof.

Abstract: The methods and compositions of the disclosure provide for novel therapeutic compounds to treat obesity and aspects related thereto. Embodiments of the disclosure relate to oligonucleotide therapeutic (ONT) agents targeting miR-22 miRNA for the treatment of human obesity and related cardiometabolic disorders. Accordingly, aspects of the disclosure relate to modified nucleic acids, including locked nucleic acids, ethylene-bridged nucleotides, peptide nucleic acids, phosphorodiamidate morpholino oligonucleotides, and or a 5?(E)-vinyl-phosphonate modification.

Abstract: Compositions and methods relating to modulating thermogenic regulation are disclosed. The compositions and methods can be used to treat diseases or conditions such as obesity or cardiometabolic disorders such as type 2 diabetes mellitus, NAFLD and NASH. Compositions include an adipocyte-targeting composition that includes a therapeutic agent capable of modulating thermogenic regulation, a targeting element facilitating cellular uptake and delivery of the therapeutic agent to a targeted adipocyte, and liposomal particles comprising sphingomyelin, DMPC, and cholesterol, wherein the liposomal particles enhance intra-cellular penetration of the therapeutic agent and protect the therapeutic agent from degradation.

Abstract: Provided are novel methods and compositions for the modulation of thermogenesis. Such methods are particularly advantageous in that they allow for the reduction of body fat in a subject without the subject having to adjust their caloric intake through dieting, modify their physical activity or undergo bariatric surgery. Accordingly, the methods of the invention are particularly useful for treating or preventing obesity. Also provided are methods of screening for novel agents that modulate the activity of thermogenic regulators.