Surface-Modified Polymeric Nanoparticles for Glioblastoma Therapy: A Review on Targeting Strategies and Delivery of Repurposed Drugs and Off-Label Non-Alkylating Agents

Glioblastoma (GBM) remains the most aggressive primary brain tumor, with poor outcomes under the current standard-of-care with temozolomide (TMZ). Therapeutic failure is multifactorial, mainly driven by TMZ resistance mediated by DNA repair enzymes (MGMT), and an immunosuppressive tumor microenvironment. Drug repurposing and the off-label use of chemotherapeutics have emerged as a strategy to identify non-alkylating agents capable of bypassing MGMT-mediated resistance in GBM. Despite their promise, the effective delivery of these drugs to the brain remains a major challenge due to the low-permeability nature of the blood-brain barrier (BBB). Thus, surface-modified polymeric nanoparticles (NPs) have emerged as adaptable platforms for encapsulating chemically diverse payloads, thereby improving their pharmacokinetics and enabling controlled release at the tumor site. This review critically analyzes ligand-functionalized polymeric NPs for GBM therapy and discusses the integration of repurposed and off-label non-alkylating agents with nanocarrier engineering, focusing on non-alkylating agents as they are MGMT-independent candidates. Furthermore, this review synthesizes recent advances in ligand-functionalized polymeric nanoformulations encapsulating non-alkylating agents for GBM, critically outlining their targeting and transport strategies, design and validation challenges, and future directions. Across the included studies, receptor-targeted surface engineering frequently enhances cellular uptake and in vitro efficacy.