Multidrug resistance (MDR) is a significant challenge in tumor treatment, severely reducing the effectiveness of anticancer drugs and contributing to high mortality rates. This article overviews the various factors involved in the development of MDR, such as changes in drug targets, increased DNA repair mechanisms, and the impact of the tumor microenvironment. It also emphasizes the potential of mesoporous silica nanoparticles (MSNs) as a drug delivery system to combat MDR. With their unique characteristics—such as a high surface area, adjustable pore sizes, and the ability to be functionalized for targeted delivery—MSNs serve as excellent carriers for the simultaneous delivery of chemotherapeutics and siRNAs aimed at reversing resistance pathways. The paper focuses on innovative methods using MSNs for direct intranuclear delivery of their cargos to overcome efflux barrier and improve the effectiveness of combination therapies. This review highlights a promising approach for enhancing cancer treatment outcomes by integrating advanced nanotechnology with traditional therapies, addressing the ongoing challenge of MDR in oncology.