Galactosylated iron oxide nanoplatforms for targeted imaging and ferroptosis-enhanced glioblastoma therapy <i>via</i> immune modulation

The rapid progression and diffuse nature of brain cancer demand urgent intervention and mitigation of tumor growth under imaging surveillance before definitive treatment could significantly improve therapeutic outcomes. Inspired by the ability of carbohydrates to stimulate immune activity, we developed a novel method for one-pot synthesis of galactosyl material-a biointerface to coat iron oxide nanoparticles (IONPs) with a condensed glycopolymer (CG)-like structure. These IONPs@CG facilitate multivalent interactions, allowing for the simultaneous binding of M2-like macrophages and glioblastoma (GBM) cells. Importantly, we found that the therapeutic efficacy of IONPs@CG is closely associated with the surface sugar density, where higher galactose content enhances immune reprogramming efficiency. Through galactose-mediated endocytosis, IONPs@CG upregulate NF-κB and downregulate STAT3 signaling in M2 macrophages, driving M2-to-M1 polarization. In GBM cells, IONPs@CG induce mitochondria-dependent apoptosis and suppress STAT3/NF-κB signaling, inhibiting tumor growth. Additionally, the iron content in IONPs@CG activates GPX4, triggering ferroptosis. These effects of single IONPs@CG not only localize the distribution of GBM but also systematically reprogram the immunosuppressive environment, thereby enhancing the effectiveness of immune checkpoint inhibitors (anti-PD-L1) in a GBM model. Prussian blue staining, <i>T</i>₂-weighting imaging, and isotope-labeled ¹²⁵I-IONPs@CG confirmed their selective and enhanced accumulation in brain tumors, demonstrating blood-brain barrier penetration. The galactosyl IONPs@CG nanoagent demonstrates significant potential for immune reprogramming, induction of apoptosis and ferroptosis, enhancement of immunotherapeutic efficacy, and MRI contrast imaging, offering a multifaceted approach to glioblastoma treatment.