Payload-free epitope imprinted polymer nanoparticles selectively targeting IL-13Rα2 and inhibition of diffuse midline glioma cells

Background/Objectives: Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma (DIPG), present a significant medical challenge due to their aggressive nature and poor prognosis. Widespread overexpression of the interleukin-13 receptor subunit alpha-2 (IL-13Rα2) across gliomas makes it a promising therapeutic target. Method: Using epitope mapping through a molecular imprinting (EMMI) technique, we developed nanosized molecularly imprinted polymers (nanoMIPs) that specifically recognize different IL-13Rα2 domains. Results: Functional assays showed that nanoMIPs binding to the surface of IL-13Rα2 reduced glioma cell viability, while sparing non-tumor cells. Consistent with receptor-mediated interactions, these nanoMIPs were selectively accumulated onto glioma cells, a specificity validated using a reverse-epitope nanoMIP negative control (nanoMIP-1*). IL-13Rα2-specific nanoMIPs suppressed phosphorylation of ERK1/2, AKT, and STAT3, disrupting major survival pathways. Moreover, these nanoMIPs activated the pro-apoptotic caspase-3/7 pathway, confirming apoptosis induction. Conclusions: Our findings demonstrate that IL-13Rα2-specific nanoMIPs, without a pharmacological payload, exert strong anti-proliferative and pro-apoptotic effects on DMG cells. Collectively, nanoMIPs represent a robust, reproducible synthetic antibody nanoplatform for targeted therapies in cancer and other diseases characterized by cell-surface protein dysregulation.