Self-assembling nanoparticles for miRNA delivery towards precision medicine against melanoma

Metastatic melanoma is a highly aggressive tumor with a poor prognosis. One of the therapeutic options for patients bearing BRAF V600E mutations is targeted therapy, which is based on the use of drugs able to inhibit the mitogen-activated protein kinase (MAPK) pathway. However, the long-term efficacy of targeted therapy is compromised by the onset of drug resistance. We previously identified a panel of oncosuppressor microRNAs (miRNAs) able to prevent the development of drug resistance to targeted therapy. We also developed self-assembling nanoparticles (SANP) as a promising and versatile nanomedicine platform for RNA-based personalized therapies. Here, we provide the proof-of-principle of a miRNA-based therapeutic strategy against BRAF-mutant melanomas. The role of the cationic lipid, ionizable lipid, cholesterol, and PEGylated lipid in SANP formulations was investigated to optimize miRNA encapsulation and delivery to melanoma cells. miRNA-loaded SANPs inhibited the release of soluble tumor-promoting factors and prevented the proliferation of metastatic melanoma cells. When used in combination with targeted therapy, miRNA-SANPs were able to potentiate its efficacy in a dose-response manner. These results pave the way for further studies on SANP as a platform for miRNA delivery to prevent the development of resistance to targeted therapy in metastatic melanoma.