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Glioblastoma (GB) is the most common and aggressive brain tumor. The treatment for newly diagnosed glioblastoma is surgical resection of the primary tumor mass, followed by radiotherapy and chemotherapy. However, recurrences frequently occur in proximity to the surgical resection area. In these cases, none of the current therapies is effective. Recently, implantable biomaterials seem to be a promising strategy against GB recurrence. Here, for the first time we combined the tailorable properties of soy-protein hydrogels with the versatility of drug-loaded liposomes to realize a hybrid biomaterial for controlled and sustained nanoparticles release. Hydrogel consisting of 18–20 % w/v soy-protein isolated were fabricated in absence of chemical cross-linkers. They were biodegradable (−10 % and −30 % of weight by hydrolytic and enzymatic degradation, respectively in 3 days), biocompatible (>95 % of cell viability after treatment), and capable of sustained release of intact doxorubicin-loaded liposomes (diffusion coefficient between 10−18 and 10 −19 m2 s−1). A proof-of-concept in a “donut-like” 3D-bioprinted model shows that liposomes released by hydrogels were able to diffuse in a model with a complex extracellular matrix-like network and a 3D structural organization, targeting glioblastoma cells. The combination of nanoparticles' encapsulation capabilities with the hydrogels' structural support and controlled release properties will provide a powerful tool with high clinical relevance that could be applicable for the treatment of other cancers, realizing patient-specific interventions.

Glioblastoma is the most common and aggressive brain tumor, associated with poor prognosis and survival, representing a challenging medical issue for neurooncologists. Dysregulation of histone-modifying enzymes (HDACs) is commonly identified in many tumors and has been linked to cancer proliferation, changes in metabolism, and drug resistance. These findings led to the development of HDAC inhibitors, which are limited by their narrow therapeutic index. In this work, we provide the proof of concept for a delivery system that can improve the in vivo half-life and increase the brain delivery of Givinostat, a pan-HDAC inhibitor. Here, 150-nm-sized liposomes composed of cholesterol and sphingomyelin with or without surface decoration with mApoE peptide, inhibited human glioblastoma cell growth in 2D and 3D models by inducing a time-and dose-dependent reduction in cell viability, reduction in the receptors involved in cholesterol metabolism (from −25% to −75% of protein levels), and reduction in HDAC activity (−25% within 30 min). In addition, liposome-Givinostat formulations showed a 2.5-fold increase in the drug half-life in the bloodstream and a 6-fold increase in the amount of drug entering the brain in healthy mice, without any signs of overt toxicity. These features make liposomes loaded with Givinostat valuable as potential candidates for glioblastoma therapy.