Background With an average survival time of just 14 months post-diagnosis, and a 5-year survival rate of about 5%, glioblastoma multiforme (GBM) represents the most aggressive brain cancer and one of deadliest human cancer. Its efficient treatment is hindered by several factors, including the highly infiltrative nature of GBM, resulting into incomplete surgical resection, and the limited delivery of therapeutics across the blood-brain-barrier (BBB). Nanomedicine could be an extremely promising curative option; however, there is still urgent need for solutions aiming at a precise and personalized therapy, in particular considering the inter-tumoral variability of GBM. Hypothesis A therapeutic nanoplatform based on lipid magnetic nanovectors loaded with a drug and modified with patient-specific cancer cell membranes is expected to work as drug delivery system able to specifically recognize cancer cells, owing to membrane-membrane homotypic targeting after blood-brain barrier crossing. The chemotherapy, personalized on the basis of the specific response of cells from each patient, is reinforced by hyperthermia, arising from the magnetic properties of the nanovectors upon application of alternating magnetic fields. This synergic approach is supposed to drastically improve therapeutic efficiency, while the homotypic targeting will grant a personalized and precision nanomedicine. Aims The main goal of this project is the elaboration of a new personalized therapeutic strategy against GBM. The specific aims can be summarized in: i) the achievement of small library of biocompatible, patient-personalized, and drug-loaded cell membrane-coated lipid magnetic nanovectors, able to efficiently target GBM cells owing to homotypic membrane-membrane recognition; ii) the obtainment of a synergic cancer therapy protocol, based on both hyperthermia and on the chemotherapeutic agent, with the latter to be chosen based on the response of the patient’s cells following treatment with various therapeutic molecules. Experimental Design The starting step of the project is the synthesis and characterization of drug-loaded membrane-coated lipid magnetic nanovectors. Patient-derived samples will be deployed to extract cell membranes for nanovector decoration; moreover, patient’s cells will be used to establish cell cultures for in vitro models and patient-specific in vivo xenografts. Thereafter, extensive in vitro experiments will be performed in order to assess BBB crossing, targeting, and therapeutic effects (due to the chemotherapy, to the hyperthermia, and to their synergic effects); the system will be eventually validated in vivo. Proteomics will be exploited to corroborate findings and to provide an insight of the mechanisms underlying the observed phenomena. Expected Results An improvement of therapeutic procedures against GBM is expected upon successful project completion, with a 2-fold increment of the specific nanovector accumulation with respect to traditional strategies and a ≥ 50% decrement of the chemotherapy drug dose, thus also drastically avoiding side-effects on healthy tissues. This precision personalized approach will address the remarkable inter-tumoral heterogeneity of GBM, and would represent a disruptive unconventional paradigm in the treatment of cerebral neoplastic pathologies. Impact on Cancer Impact will be appreciable both in a short-term scenario, with new molecular knowledge about the mechanisms of action of different drugs in different patient-derived models, and in a mid/long-term scenario, thus leading to a realistic exploitation of the proposed nanovectors in the future clinical practice.