An ionic liquid-based delivery system of small interfering RNA targeting Bcl-2 for melanoma therapy†

Abstract

Melanoma, characterized by rapid tumour progression and a strong tendency to metastasize, poses significant challenges in clinical treatment. Given the vital role of B-cell lymphoma 2 (Bcl-2) protein overexpression in inhibiting apoptosis in tumour cells, the suppression of Bcl-2 has emerged as a promising anticancer therapy. Here, we have developed a straightforward and effective delivery system that combines small interfering RNA (siRNA) targeting Bcl-2 (siBcl-2) with ionic liquids (ILs) for treating melanoma. The unique properties of ILs including structural tunability, inherent charge, and chemical stability have garnered significant attention in the biomedical fields; however, their application in siRNA delivery remains nascent. Rather than the weak function of free siBcl-2, our delivery system (1-hexyl-3-methylimidazolium-siBcl-2, designated as C6-siBcl-2) demonstrated an outstanding capacity to improve the cellular uptake and lysosomal escape, resulting in robust apoptosis and cytotoxicity in melanoma cells. In addition to exhibiting superior gene silencing activity in vitro, such events were also evident in mice bearing melanoma tumours. In particular, this IL-based delivery system showed advantages in suppressing tumour growth, preventing metastasis, and enhancing the survival time of mice with melanoma tumours. Therefore, our study offered a novel and powerful nanoplatform that integrated ILs and RNA interference therapy, presenting new strategies for cancer treatment.