Pancreatic ductal adenocarcinoma (PDAC) is an intractable malignancy with a dismal survival rate. Recent combination therapies have had a major impact on the improvement of PDAC prognosis. Nevertheless, clinically used combination regimens such as FOLFIRINOX and gemcitabine (Gem)/nab-paclitaxel still face major challenges due to lack of the safe and ratiometric delivery of multiple drugs. Here, a rationally designed mesoporous silica nanoparticle (MSN)-based platform is reported for the target-specific, spatiotemporal, ratiometric, and safe co-delivery of Gem and cisplatin (cisPt). It is shown that systemic administration of the nanoparticles results in synergistic therapeutic outcome in a syngeneic and clinically relevant genetically engineered PDAC mouse model that has rarely been used for the therapeutic evaluation of nanomedicine. This synergism is associated with a strategic engineering approach, in which nanoparticles provide redox-responsive controlled delivery and in situ differential release of Gem/cisPt drugs with the goal of overcoming resistance to Pt-based drugs. The platform is also rendered with additional tumor-specificity via a novel tumor-associated mucin1 (tMUC1)-specific antibody, TAB004. Overall, the platform suppresses tumor growth and eliminates the off-target toxicities of a highly toxic chemotherapy combination.