Mesoporous Silica Nanoparticles With Customized Drug Ratio/Loading for Effective Treatment of Gemcitabine‐Resistant Pancreatic Tumors

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a 5‐year survival rate below 13% and limited treatment options due to rapid metastasis and pronounced chemoresistance. Gemcitabine (Gem) remains a first‐line chemotherapy agent; however, its clinical efficacy is hindered by poor cellular uptake, incomplete activation, and acquired drug resistance. To address these limitations, we develop redox‐responsive mesoporous silica nanoparticles (MSNs) for the mono‐ and codelivery of Gem and Cisplatin (cisPt). In this work, we tune the loading and ratio of Gem and cisPt within MSNs. To evaluate the therapeutic potential of MSN‐based delivery system in Gem‐resistant (GR) PDAC cell lines, we establish murine (GR‐KCM) and human (GR‐BxPC3) cell models and further evaluate the efficacy in highly GR human cell lines (AsPC1 and HPAFII). In vitro studies demonstrate that Gem‐MSNs (10%wt) and Gem‐cisPt‐MSN (10:9%wt) exhibit the strongest cytotoxicity, even in GR models. Notably, the combination Gem‐cisPt‐MSN (18:9%wt) induces pronounced S‐phase cell cycle arrest, apoptosis, and reactive oxygen species. These findings underscore the potential of MSN‐based drug delivery systems to enhance chemotherapy efficacy in treatment‐refractory PDAC.