Abstract: The present disclosure provides a lipid nanoparticle comprising encapsulated mRNA and at least 30 mol % of a sphingolipid (e.g. sphingomyelin (SM)), 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 2-fold increase in gene expression in the liver, spleen and/or bone marrow at 4 or 24 hours post-injection as compared to a lipid nanoparticle encapsulating mRNA with an Onpattro™-type formulation of cationic, ionizable lipid/DSPC or ESM/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). Further provided are methods of medical treatment and uses of such lipid nanoparticles to treat or prevent a disease condition in a hepatic or non-hepatic tissue or organ.

Abstract: Provided are photoswitchable glycerophospholipids having a photoswitchable group having the following structure: or The photoswitchable glycerophospholipids can be isomerized by red spectral light. Also disclosed are nanovesicles (e.g., liposomes). Also disclosed are methods of making the photoswitchable glycerophospholipids and nanovesicles formed therefrom. The present disclosure further provides methods of using the nanovesicles. e.g., for targeted delivery of cargo. A photoswitchable glycerophospholipid may have the following structure: Structure I.