Multiparametric CEST MRI–Guided Intranasal Theranostic Liposomes for Quantitative Biodistribution and Response Prediction in Glioblastoma

Abstract Glioblastoma (GBM) treatment is limited by the blood-brain-barrier(BBB) and lack of non-invasive methods to track drug delivery and therapeutic response simultaneously. We developed a theranostic strategy utilizing multiparametric chemical exchange saturation transfer(CEST) MRI to guide the nose-to-brain delivery of mucus-penetrating liposomes encapsulating gemcitabine and iohexol(1:1; Gem/Ioh-Lipo). These multiple CEST contrast indicated drug-specific signals (gemcitabine 2.4 ppm, iohexol 4.3 ppm and liposome − 3.5 ppm), demonstrating that > 70% intranasal dose reached the frontal cortex from the olfactory bulb.Importantly, CEST at 4.3 ppm strongly correlated with tumor response(R² > 0.9), indicating the prognostic value of image-guidance. Another CEST contrast (APTw at 3.5 ppm) indicated the tumor response, intranasal Gem/Ioh-Lipo produced an 8.6-fold tumor volume reduction versus drug-free liposomes (P < 0.0001). Controls showed a 55.9% increase in APTw signal in tumor (P < 0.005), indicating increased cellularity and proliferating cells, which were absent in treated animals. This CEST MRI-guided theranostic strategy enables non-invasive, real-time quantification of drug biodistribution and therapeutic efficacy for GBM, enabling precise treatment evaluation.