Modular Design of Mesoporous Silica Nanoparticles Enables Bioimaging, Dual Chemotherapy, and Combinatorial Gene Silencing in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) accounts for 10-15% of all breast cancers and remains the most aggressive subtype due to its resistance to standard chemotherapy. A key factor behind its resistance is the activation of antiapoptotic pathways, which help tumor cells evade drug-induced death. We present a modular platform for combinatorial therapy, simultaneously delivering different clinically approved chemotherapeutics and RNAi agents targeting multiple survival pathways in vitro. To ensure that therapeutic activation occurs only after cellular uptake, mesoporous silica nanoparticles were functionalized with cisplatin and gemcitabine via reduction-sensitive linkers, while surface modification with polyethylenimine enabled pH-responsive release of programmable RNA nanoparticles that, upon intracellular dicing, produce DS RNAs targeting the expression of Survivin and BCL-2. This optimized formulation achieved strong gene silencing, minimized immune activation, and enhanced cytotoxicity in TNBC cells compared to either treatment alone. The results highlight the potential of this combinatorial strategy to overcome chemoresistance by delivering multiple therapeutics that simultaneously target distinct survival pathways in cancer cells and can be readily modified and adapted to new targets.