Abstract: Defined multi-conjugate oligonucleotides can have predetermined sizes and compositions. For example, in various embodiment, defined multi-conjugate oligonucleotides can have advantageous properties, for example in the form of defined multi-conjugate siRNA (i.e., including two, three or more siRNA) having enhanced intracellular delivery and/or multi-gene silencing effects. In various embodiment, the defined multi-conjugate oligonucleotides can be synthesized via new synthetic intermediates and methods. The defined multi-conjugate oligonucleotides can be used, for example, in reducing gene expression, biological research, treating or preventing medical conditions, or to produce new or altered phenotypes in cells or organisms.

Abstract: Defined multi-conjugate oligonucleotides can have predetermined sizes and compositions. For example, in various embodiment, defined multi-conjugate oligonucleotides can have advantageous properties, for example in the form of defined multi-conjugate siRNA (i.e., including two, three or more siRNA) having enhanced intracellular delivery and/or multi-gene silencing effects. In various embodiment, the defined multi-conjugate oligonucleotides can be synthesized via new synthetic intermediates and methods. The defined multi-conjugate oligonucleotides can be used, for example, in reducing gene expression, biological research, treating or preventing medical conditions, or t9o produce new or altered phenotypes in cells or organisms.

Abstract: Compositions for delivering nucleic acids to cells or tissue microenvironments are provided. In one embodiment, the compositions are lipid nanoparticle compositions formulated to have reduced splenic and hepatic clearance. It has been discovered that the chemical composition of lipid nanoparticles significantly influences the natural trafficking of the lipid nanoparticles. More specifically, it has been discovered that conformationally constrained ionizable lipids can modify the tropism and clearance profile of lipid nanoparticles without the need of a targeting ligand. It has also been discovered that tropism of the disclosed lipid nanoparticles is size-independent.

Abstract: Compositions and methods for inactivating RNA-guided genome editing systems in specific tissue, for example hepatocytes, are provided herein. In one embodiment, the compositions are small chemically modified oligonucleotides that can target and bind to guide RNA, thus eliminating the ability of guide RNA to interact with an endonuclease. The disclosed oligonucleotides are delivered in lipid nanoparticles formulated to target a specific tissue. Subsequently delivered RNA-guided genome editing systems will be inhibited in the specific tissue that received the oligonucleotides. The disclosed compositions and methods allow for reduced RNA-guided genome editing in hepatocytes.

Abstract: Defined multi-conjugate oligonucleotides can have predetermined sizes and compositions. For example, in various embodiment, defined multi-conjugate oligonucleotides can have advantageous properties, for example in the form of defined multi-conjugate siRNA (i.e., including two, three or more siRNA) having enhanced intracellular delivery and/or multi-gene silencing effects. In various embodiment, the defined multi-conjugate oligonucleotides can be synthesized via new synthetic intermediates and methods. The defined multi-conjugate oligonucleotides can be used, for example, in reducing gene expression, biological research, treating or preventing medical conditions, or to produce new or altered phenotypes in cells or organisms.

Abstract: Defined multi-conjugate oligonucleotides can have predetermined sizes and compositions. For example, in various embodiment, defined multi-conjugate oligonucleotides can have advantageous properties, for example in the form of defined multi-conjugate siRNA (i.e., including two, three or more siRNA) having enhanced intracellular delivery and/or multi-gene silencing effects. In various embodiment, the defined multi-conjugate oligonucleotides can be synthesized via new synthetic intermediates and methods. The defined multi-conjugate oligonucleotides can be used, for example, in reducing gene expression, biological research, treating or preventing medical conditions, or to produce new or altered phenotypes in cells or organisms.