Neutral Nanocomplex Delivers Plasmid Encoding α-Hemolysin for Uveal Melanoma Treatment

Abstract

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Currently, the efficacy of existing eye-preserving local treatments for primary UM is unsatisfactory, expressing a need to explore a new therapy for UM treatment. α-Hemolysin (Hla), a pathogenic toxin fom Staphylococcus aureus, can induce cell death by disrupting the cell membrane and has potential antitumor effects. However, the broad toxicity of Hla limits its application in tumor therapy. In this study, the Hla-based gene therapy strategy that uses plasmids to encode the Hla gene and applies tumor-targeting nanoparticles to load the plasmids to form a nanocomplex is proposed. This gene formulation can overcome the obstructions of ocular barriers with its favorable neutral surface charge and nano size, allowing for precise targeting of tumor cells after local administration. The nanocomplex can effectively transfect tumor cells, and the expression of Hla can significantly inhibit tumor growth and directly exert a killing effect. Moreover, the nanocomplex can enhance the antitumor effect by recruiting CD4⁺ and CD8⁺ T lymphocytes and reducing angiogenesis after local administration. The study provides a novel gene therapy strategy for primary UM treatment and demonstrates a potential application for future gene therapy in intraocular tumors.