Patient‐Personalized Membrane‐Coated Magnetic Nanovectors: Probing the Biomimetic Interface for Targeted Tumor Theranostics

Achieving selective tumor targeting remains a major challenge in heterogeneous tumors like glioblastoma (GBM), the most aggressive brain cancer. To address this, cell‐derived magnetic nanovectors, hybrid lipid nanoparticles integrating iron oxide nanoparticles (IONPs) cloaked with plasma membranes from patient‐derived GBM cells, were introduced. This nanoarchitecture exploits homotypic recognition to combine magnetic hyperthermia with magnetic resonance imaging (MRI) contrast within a customizable theranostic platform. However, preserving membrane protein conformation during nanoparticle fabrication remains a challenge that affects targeting specificity. In this work, a label‐free spectroscopic platform combining fluorescence emission, Fourier transform infrared spectroscopy, and Raman spectroscopy was developed to probe protein conformation at the nanoparticle interface. With this approach, an optimized ultrasonication protocol was shown to ensure protein integrity, enabling homotypic interactions and preventing hard protein corona formation, a determinant of nanoparticle fate in biological environments. Consistent with these findings, preserved membrane proteins enhance nanoparticle accumulation in patient‐derived GBM spheroids and support MRI contrast performance. Additionally, oxidative stress in cells upon IONP internalization induces a compensatory increase in glycolytic metabolism, underscoring the importance of tumor specificity to reduce off‐target effects. This work provides a framework for probing protein conformation on nanoparticles, aiding the refinement of biomimetic nanotheranostics for precision GBM treatment.