Multifunctional hybrid nanoparticles are being developed to carry a wide variety of therapeutic and imaging agents for multiple biomedical applications. Polysilsesquioxane (PSilQ) nanoparticles are a promising hybrid platform with numerous advantages to be used as a delivery system. In this report, we demonstrate the ability of a stimuli-responsive PSilQ-based platform to transport and deliver simultaneously protoporphyrin IX, curcumin, and RNA interference inducers inside human cells. This multimodal delivery system shows a synergistic performance for the combined phototherapy and chemotherapy of triple-negative breast cancer and can be used for efficient transfection of therapeutic nucleic acids. The current work represents the first report of using the PSilQ platform for the combined phototherapy and chemotherapy and gene delivery.