Ultrasmall Iron Oxide as an Imaging Nanoenzyme Loaded Autologous Exosomes for Targeted Imaging and Chemotherapy Promotion of Pancreatic Cancer.

Pancreatic cancer presents significant imaging challenges due to its poor vascularization, while the hypoxic tumor microenvironment further contributes to chemoresistance. To address these limitations, we engineered exosome-ultrasmall iron oxide (Exo-USIO), a targeted exosomal nanoprobe encapsulating USIO nanoparticles (USIO NPs), designed to enable precise tumor imaging and enhance chemotherapy efficacy in pancreatic cancer. Exosomes derived from Panc-02 pancreatic cancer cells were isolated and loaded with USIO NPs via electroporation to synthesize Exo-USIO. The nanoprobe's targeting specificity, MRI contrast enhancement, and catalase-like activity (converting H2O2 to O2) were systematically evaluated. In vitro assays assessed cellular uptake, hypoxia modulation, and chemosensitivity, while in vivo studies validated tumor-targeted MRI imaging, hypoxia alleviation, and synergistic therapeutic effects with gemcitabine (GEM). Exo-USIO demonstrated a 2.3-fold increase in T1-weighted MRI signal intensity compared to free USIO NPs (P < 0.01), alongside efficient enzymatic conversion of H2O2 to O2, significantly reducing HIF-1α expression (P < 0.05). Combined with GEM, Exo-USIO reduced tumor cell viability to 39.8% in vitro and suppressed tumor growth by 62% in vivo (P < 0.001). Biosafety evaluations revealed negligible systemic toxicity or metastatic risk. By leveraging exosome-mediated targeted delivery and the dual enzyme-mimetic activity of USIO NPs, Exo-USIO achieves dual functionality: enhanced MRI-guided tumor localization and catalytic alleviation of hypoxia to reverse chemoresistance. This strategy overcomes key limitations of the pancreatic tumor microenvironment, offering a translatable platform for precision theranostics.