Advances in PLGA-Based Drug Delivery Systems for Glioblastoma Treatment.

Glioblastoma (GBM) is the most aggressive primary brain tumor, with median survival rates remaining dismally low despite standard-of-care therapies including maximal resection, radiation, and chemotherapy. A significant challenge in GBM therapy is the inability of conventional drugs to achieve therapeutic concentrations in the tumor due to the restrictive nature of the blood-brain barrier (BBB) and the complex tumor microenvironment (TME), which includes high interstitial pressure, abnormal vasculature, and dense extracellular matrix that together hinder drug penetration and distribution. Nanoparticle-based drug delivery systems have emerged as promising tools to circumvent the BBB and enhance drug delivery for GBM treatment. Among these, poly(lactic-co-glycolic acid) (PLGA) formulations stand out as one of the most widely used biodegradable carriers, which have been approved by the FDA for drug delivery applications. This review provides a comprehensive evaluation of the challenges and opportunities arising from the GBM microenvironment and their implications for the development of PLGA nanoparticle-based drug delivery systems. We compare commonly used PLGA nanoparticle synthesis techniques and analyze key GBM characteristics that impede drug transport, highlighting how tumor microenvironmental constraints govern nanoparticle engineering and delivery efficiency. We further evaluate the integration of multimodal therapies that affect both therapeutic delivery and outcomes. Critically, we identify persistent translational bottlenecks and outline specific research and engineering solutions to bridge preclinical efficacy and clinical translation. By integrating current evidence through a translational perspective, this review offers researchers and clinicians a strategic roadmap to guide future efforts toward more rational nanoparticle design and successful clinical translation for GBM therapy.