Nanoformulations Downregulating METTL16 Combined with mRNA Tumor Vaccines Suppress Triple-Negative Breast Cancer and Prevent Metastasis.

PURPOSE: Triple-negative breast cancer (TNBC) poses a significant threat to women's health due to its high malignancy and recurrence. Traditional treatments such as surgical resection, radiotherapy, and chemotherapy are no longer sufficient to meet clinical needs. Based on prior research that identified METTL16 as a potential target for TNBC, this study aimed to develop a nanoformulation to mitigate the malignancy of TNBC by silencing METTL16. The integration of this formulation with emerging mRNA tumor vaccines aimed to effectively inhibit the growth and metastasis of TNBC. RESEARCH METHODS: Using microfluidic technology, efficient siRNA encapsulation in lipid nanoparticle (LNP) yielded LNP/siMETTL16 and selective organ-targeting LNP/siMETTL16 (SORT-LNP/siMETTL16). Initially, the antitumor properties of LNP/siMETTL16 were evaluated at the cellular level. Subsequently, the antitumor properties were explored in mouse subcutaneous TNBC models with LNP/siMETTL16 (intratumoral injection) and mRNA tumor vaccines (intramuscular injection). The combined inhibition of TNBC lung metastasis by SORT-LNP/siMETTL16 (intravenous injection) and mRNA vaccine (intramuscular injection) was also investigated. RESULTS: Cellular experiments demonstrated the efficient silencing effect of LNP/siMETTL16, leading to inhibition of tumor cell activity. The combination of LNP/siMETTL16 and LNP/mMUC1 significantly suppressed subcutaneous tumor growth, achieving an inhibition rate of 66.0%. Furthermore, the combination of SORT-LNP/siMETTL16 and mRNA tumor vaccines markedly alleviated TNBC lung metastasis. CONCLUSION: This study provides evident support for the application and translation of METTL16 as a therapeutic target and offers a novel strategy for TNBC combined treatment in clinical settings.