Protease-responsive mesoporous silica nanoparticles for the targeted treatment of pancreatic cancer

Pancreatic Ductal Adenocarcinoma (PDAC) remains a formidable challenge, with reported 5-year survival rates of 8%. This limited survival is partly due to the constraints of current chemotherapy regimens, which are often curtailed by dose-limiting toxicities. Targeted delivery systems may reduce off-target effects. PDAC is characterized by a pronounced desmoplastic reaction, a complex microenvironment with aberrant protease activity. This feature prompted us to investigate protease-mediated targeted delivery as a novel therapeutic approach for PDAC. In this thesis, we describe the first protease-responsive mesoporous silica nanoparticles (MSNs) specifically designed for PDAC treatment. We engineered MSNs to be responsive to both extracellular and intracellular proteases and demonstrated that intracellular-responsive MSNs offer the most promising results. Preclinical evaluations in various in vitro and in vivo models revealed that CAPN2-responsive MSNs not only reduced side effects but also enhanced antitumor efficacy compared to free drugs. In conclusion, we pioneered the development of protease activity-responsive nanoparticles, demonstrating their potential for treating PDAC.