Significance: The current application of messenger RNA (mRNA)-based technology has largely been confined to liver diseases because of the lack of a specific and efficient extrahepatic in vivo systemic mRNA delivery system. Here, we have developed a library of N-series lipid nanoparticles (LNPs) that could specifically regulate the protein composition of protein corona on the surface of LNPs, which allows specific delivery of mRNA to the lung. We further demonstrated that our lung-targeting LNP could effectively deliver mouse tuberous sclerosis complex 2 ( Tsc2 ) mRNA into TSC2-null cells and restore its function, resulting in enhanced control of tumor burden in a preclinical model of lymphangioleiomyomatosis, a destructive lung disease caused by loss-of-function mutations in the Tsc2 gene.

Significance: Genome editing technologies enable the permanent repair of disease-causing genetic mutations. However, the application of this technology has been limited by the technical challenge of achieving safe, effective, and specific in vivo delivery of the CRISPR-Cas9 genome editing components. Here, we report the development of a newly identified lipid nanoparticle (LNP) for specific delivery of CRISPR-Cas9 mRNA to the liver. While LNPs have been FDA approved for delivery of siRNA to the liver, here we examine their application for genome editing. When compared head-to-head, our delivery platform significantly outperforms the FDA-approved LNP in the efficient delivery of Cas9 mRNA for knockdown of theAngptl3gene and subsequent regulation of hypercholesterolemia, while matching the safety and specificity of the approved platform.

Tryptamine-derived lipidoid-doped lipid nanoparticle formulations facilitate cargos crossing the blood-brain barrier.

To develop biocompatible reduction-responsive micellar systems for efficient intracellular drug delivery, disulfide-linked block copolymers of methoxyl poly(ethylene glycol) (mPEG) and poly(ε-benzyloxycarbonyl-L-lysine) (PZLL) were synthesized through ring-opening polymerization of ε-benzyloxycarbonyl-L-lysine N-carboxyanhydride with amino group terminated disulfide functionalized mPEG as macroinitiator. The copolymers self-assembled into micelles in phosphate buffered saline (PBS) at pH 7.4 through direct dissolution and dialysis methods. The micelles were revealed to have excellent hemocompatibilities, and cell and tissue compatibilities, which rendered them with potential for drug delivery applications. Doxorubicin (DOX), an anthracycline antitumor drug, was loaded into the micelles through nanoprecipitation with a drug loading efficiency of about 30 wt%. The in vitro DOX release from all DOX-loaded micelles was accelerated in PBS with 10.0 mM GSH, mimicking intracellular reductive conditions. DOX-loaded micelles showed higher cellular proliferation inhibition towards glutathione monoester pretreated HeLa (a human cervical cell line) and HepG2 cells (a human hepatoma cell line) as compared to unpretreated or buthionine sulfoximine pretreated cells. The above results indicated that the biocompatible reduction-responsive micelles have vast potential in targeted intracellular delivery of antitumor drugs to achieve enhanced efficacy in malignancy therapy.