Sphk2 RNAi nanoparticles suppress tumor growth via downregulating cancer cell derived exosomal microRNA

Exosomes secreted from cancer cells promote tumor progression through the transfection of containing microRNA (miRNA), mRNAs and proteins. Yet, little of this knowledge has translated into the therapeutic application. Herein, we propose a tumor therapeutic strategy via decreasing exosomal miRNA secretion. The study designed small interfering RNA (siRNA) loaded nanoparticles to downregulate sphingosine kinase 2 (Sphk2) and investigate their potential in decreasing exosomal oncogenic miRNA content and inhibiting tumor growth. The synthesized lipid (2E)-4-(dioleostearin)-amino-4-carbonyl-2-butenoic (DC) and chitosan were utilized to produce siRNA loaded nanoparticles (DC/CS-siRNA NPs), with optimal siRNA complexation and high transfection efficacy. We demonstrated that Sphk2 gene silencing induced by nanoparticles in hepatocellular carcinoma (HCC) cells could reduce miRNA-21 sorting into exosomes, contributing to the inhibition of tumor cell migration and tumorigenic function of exosomes to normal liver cells. Furthermore, in xenograft mouse model, Sphk2 siRNA loaded DC/CS NPs could significantly block tumor progression of malignancy HCC. These results suggest a new therapeutic approach for tumor treatment by ablating oncogenic miRNA in malicious exosomes.