MUC1 Aptamer‐Capped Mesoporous Silica Nanoparticles for Navitoclax Resistance Overcoming in Triple‐Negative Breast Cancer

Abstract Triple‐negative breast cancer (TNBC) is the most aggressive breast cancer subtype. In the last years, navitoclax has emerged as a possible treatment for TNBC. Nevertheless, rapid navitoclax resistance onset has been observed thorough Mcl‐1 overexpression. As a strategy to overcome Mcl‐1‐mediated resistance, herein we present a controlled drug co‐delivery system based on mesoporous silica nanoparticles (MSNs) targeted to TNBC cells. The nanocarrier is loaded with navitoclax and the Mcl‐1 inhibitor S63845 and capped with a MUC1‐targeting aptamer ( apMUC1‐MSNs(Nav/S63845) ). The apMUC1‐capped nanoparticles effectively target TNBC cell lines and successfully induce apoptosis, overcoming navitoclax resistance. Moreover, navitoclax encapsulation protects platelets against apoptosis. These results point apMUC1‐gated MSNs as suitable BH3 mimetics nanocarriers in the targeted treatment of MUC1‐expressing TNBC.