Abstract

Uveal melanoma (UM) is a rare and highly aggressive intraocular malignancy, in which the key oncogenic driver Yes-associated protein (YAP) is persistently activated due to loss of upstream Hippo kinases, including Large Tumor Suppressor Kinase 1 (LATS1). The LATS1/YAP axis thus represents a critical therapeutic target, and restoring LATS1 activity offers a promising intervention strategy. In this study, we developed an mRNA-based therapeutic approach targeting the LATS1/YAP axis for UM treatment. Lentivirus-mediated overexpression confirmed that exogenous LATS1 suppresses YAP activity in UM cells. Delivery of in vitro transcribed LATS1 mRNA inhibited UM cell proliferation in a dose-dependent manner. To overcome ocular drug delivery challenges, we compared two lipid nanoparticle (LNP) formulations with different ionizable lipids SM102   and MC3 for intraocular mRNA delivery. The results showed SM102-based LNPs exhibited superior mRNA translation efficiency compared to MC3-LNPs in an orthotopic UM mouse model. Intraocular distribution analysis further revealed that the delivered mRNA was predominantly detected in tumor cells, with additional expression observed in Müller glial cells. Finally, intravitreal administration of LATS1 mRNA-loaded SM102-LNPs demonstrated significant suppression to the orthotopic tumor growth. These findings establish mRNA-based restoration of LATS1 via LNPs as a promising therapeutic strategy for UM.