Magic™ Mouse Anti-Human LCN2 monoclonal antibody, clone N92533-C

Triple-negative breast cancer (TNBC), which has the highest mortality rate of all breast cancer, is in urgent need of a therapeutic that hinders the spread and growth of cancer cells. CRISPR genome editing holds the promise of a potential cure for many genetic diseases, including TNBC; however, its clinical translation is being challenged by the lack of safe and effective nonviral delivery systems for in vivo therapeutic genome editing. Here we report the synthesis and application of a noncationic, deformable, and tumor-targeted nanolipogel system (tNLG) for CRISPR genome editing in TNBC tumors. We have demonstrated that tNLGs mediate a potent CRISPR knockout of Lipocalin 2 (Lcn2), a known breast cancer oncogene, in human TNBC cells in vitro and in vivo. The loss of Lcn2 significantly inhibits the migration and the mesenchymal phenotype of human TNBC cells and subsequently attenuates TNBC aggressiveness. In an orthotopic TNBC model, we have shown that systemically administered tNLGs mediated >81% CRISPR knockout of Lcn2 in TNBC tumor tissues, resulting in significant tumor growth suppression (>77%). Our proof-of-principle results provide experimental evidence that tNLGs can be used as a safe, precise, and effective delivery approach for in vivo CRISPR genome editing in TNBC.

Lipocalin-2 (LCN2), also known as 24p3 and neutrophil gelatinase-associated lipocalin (NGAL), is a 25-kDa secreted protein implicated in various metabolic and inflammatory diseases. Early studies suggest the protective function of LCN2 in which it acts as a bacteriostatic agent that competes with bacteria for iron-bound siderophores. However, both detrimental and beneficial roles of LCN2 have recently been documented in metabolic and neuroinflammatory diseases. Metabolic inflammation, as observed in diabetes and obesity, has been closely associated with the upregulation of LCN2 in blood plasma and several tissues in both humans and rodents, suggesting its pro-diabetic and pro-obesogenic role. On the contrary, other studies imply an anti-diabetic and anti-obesogenic role of LCN2 whereby a deficiency in the Lcn2 gene results in the impairment of insulin sensitivity and enhances the high-fat-diet-induced expansion of fat. A similar dual role of LCN2 has also been reported in various animal models for neurological disorders. In the midst of these mixed findings, there is no experimental evidence to explain why LCN2 shows such a contrasting role in the various studies. This debate needs to be resolved (or reconciled) and an integrated view on the topic is desirable. Herein, we attempt to address this issue by reviewing the recent findings on LCN2 in metabolic disorders and assess the potential cellular or molecular mechanisms underlying the dual role of LCN2. We further discuss the possibilities and challenges of targeting LCN2 as a potential therapeutic strategy for metabolic disorders and neurological complications.