Postoperative glioblastoma management: from relapse mechanisms and clinical interventions to emerging drug delivery strategies.

Abstract

Postoperative recurrence remains the principal cause of treatment failure in glioblastoma (GBM). Its development is driven by infiltrative residual tumor cells, glioma stem-like cell plasticity, therapy-resistant clones, dynamic blood-brain barrier (BBB)/blood-brain tumor barrier (BBTB) remodeling, and a wound-healing-associated immunosuppressive microenvironment. These factors create a distinct therapeutic window after surgery, during which tumor burden is minimal but residual disease rapidly acquires conditions favorable for regrowth. Drug delivery systems must go beyond enhanced intracranial drug accumulation; they should provide spatial coverage of the resection margin, sustained therapeutic exposure before adjuvant therapy begins, and active regulation of the evolving postoperative microenvironment. This review summarizes the clinical and biological basis of postoperative GBM recurrence and discusses delivery strategies designed to address these challenges. Established intracranial approaches and emerging local platforms, including injectable hydrogels, electrospun scaffolds, 3D-printed implants, microneedles, as well as intranasal systems, are analyzed with respect to cavity adaptation, tissue penetration, release control, and microenvironmental modulation. Systemic nanocarriers, cell-mediated delivery systems, and extracellular vesicle-based platforms are further discussed as complementary strategies for targeting infiltrative or distant tumor foci beyond the surgical cavity. Finally, we highlight integrated delivery systems combining local retention, systemic targeting, programmable release, and microenvironmental regulation to improve postoperative GBM therapy.