Doxorubicin Nanocarriers in Glioblastoma Therapy: Advances and Limitations

Glioblastoma (GBM) remains one of the most aggressive brain malignancies, with limited therapeutic success largely due to the restrictive nature of the Blood-Brain Barrier (BBB) and intrinsic drug resistance mechanisms. Despite standard treatment strategies, the median survival remains approximately 16 months, underscoring the urgent need for more effective therapeutic approaches. Doxorubicin (DOX), a potent anthracycline chemotherapeutic, has demonstrated significant anticancer activity; however, its clinical application in GBM is severely hindered by poor BBB permeability, active efflux mediated by transporters such as P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), and dose-limiting systemic toxicity. To overcome these limitations, this review focuses on Drug Delivery Systems (DDS) for DOX-loaded polymeric, magnetic, proteinbased, liposome nanocarriers, dendrimers, and Extracellular Vesicles (EVs) for BBB-targeted GBM therapy. In particular, functionalised PLGA Nanoparticles (NPs), iron oxide NPs, Ferritin (Ft), Apoferritin (AFt), Bovine Serum Albumin (BSA), peptide-functionalised liposomes, PAMAM dendrimers, and exosomes have been studied in preclinical GBM models. Despite preclinical studies showing better brain delivery and anticancer activity, DOX-loaded nanocarriers exhibit varying potencies depending on their physicochemical properties and design strategies. Herein, drug loading, encapsulation efficiency, particle size, targeting ability, model systems, and administration route were examined. Key limitations, including biological barriers, physicochemical instability, and heterogeneity in experimental models, remain critical obstacles to achieving robust and reproducible outcomes across DOX-loaded nanocarriers.