Targeted inhibition of Mcl-1 in ERα+ breast cancers using Mcl-1 siRNA encapsulated in polymeric nanoparticles (si-NPs) increased tumor cell killing in LTED-selected cells and in fulvestrant-treated cells, demonstrating that anti-estrogens prime ERα+ cells for targeted Mcl-1 inhibition. Here, MCL1 is linked to neoplasm.