ATP-responsive tumor targeted lipid nanoparticle for enhanced siRNA delivery and improved treatment efficacy in melanoma

Abstract

Small interfering RNA (siRNA) plays a crucial role in tumor therapy, especially for non-druggable targets with obvious advantages. Nevertheless, its molecular weight, negative charge, and susceptibility to degradation hinder effective delivery to tumor cells for therapeutic action. Lipid nanoparticles (LNPs) serve as an excellent delivery mechanism for siRNA but still face problems such as suboptimal tumor targeting and inefficient intracellular release. To enhance melanoma treatment, we designed lipid nanoparticles modified with phenylboronic acid (PBA) for efficient delivery of siRNA targeting “undruggable” microphthalmia-associated transcription factor (MITF). This nanocarrier successfully encapsulated siRNA and improved tumor targeting by allowing phenylboronic acid to interact with sialic acid residues overexpressed in tumor cells. Furthermore, PBA-modified lipid nanoparticles facilitated the ATP-responsive release of siRNA intracellular. These two aspects enhance gene silencing efficiency. The in vivo targeting and gene silencing capabilities of PBA-modified lipid nanoparticles significantly surpassed those of unmodified LNP. Additionally, PBA-modified nanoparticles exhibited considerable anti-tumor and anti-metastatic effects in animal models, offering an alternative approach for siRNA therapy.