Chemotherapy is generally acknowledged as an effective method for pancreatic cancer (PC). However, its treatment efficacy is often compromised due to inefficient drug delivery and drug resistance propensity of tumor tissues. The purpose of this study is to design and develop a novel drug delivery system (Manganese-doped mesoporous silica nanoparticles, Mn-MSN) in which paclitaxel (PTX), a conventional chemotherapeutic agent used to effectively treat pancreatic cancer clinically. Through cross-linking with glutaraldehyde, gelatin (Ge) was encapsulated on the carrier surface, endowing the nanoparticles (Ge-Mn-MSN@PTX) with excellent biocompatibility, low hemolytic activity, and enzyme-responsive degradation. Mn was added for the following purposes: (1) catalyzing hydrogen peroxide (H2O2) to generate oxygen (O2), thereby alleviating tumor hypoxia and drug resistance; (2) depleting glutathione (GSH), inducing intracellular lipid peroxidation and ferroptosis; (3) enabling real-time monitoring of the therapeutic efficacy of the nanoparticles via magnetic resonance imaging (MRI). The experimental results demonstrated that Ge-Mn-MSN@PTX has satisfactory biosafety, antitumor activity, controlled drug release as well as imaging tracking capabilities. In the SW1990 nude mice model, the Ge-Mn-MSN@PTX effectively inhibited tumor growth by suppressing the expression of the resistance protein P-glycoprotein (P-gp) and inducing ferroptosis. In conclusion, the designed gelatin-coated Mn-MSN shows potential for application in future pancreatic cancer therapy.Copyright © 2024 Elsevier B.V. All rights reserved.