Glioblastoma (GBM) is the most common and aggressive primary brain tumor, characterized by poor prognosis and a median survival of 12–18 months despite standard therapies such as surgery, radiation, and temozolomide chemotherapy. Its high cellular heterogeneity, along with complex mechanisms of therapy resistance, presents significant challenges for effective treatment. Conventional systemic chemotherapy is limited by the blood–brain barrier (BBB), systemic toxicity, and insufficient drug penetration into the tumor microenvironment. Emerging therapeutic strategies aim to overcome these barriers through novel chemotherapeutic agents, targeted therapies, immunotherapies, and smart drug delivery systems. Endovascular drug delivery, particularly super-selective intra-arterial cerebral infusion (SSIACI), offers a minimally invasive approach to directly target the tumor vasculature, potentially increasing drug concentration at the tumor site while reducing systemic exposure. Complementary techniques, such as MR-guided focused ultrasound, hyperosmotic disruption, and nanoparticle-based carriers, are being explored to enhance BBB penetration and retention of therapeutics within the tumor. Ongoing clinical trials and translational studies provide insights into optimizing these approaches, with future directions focused on precision medicine, biomarker-driven patient selection, and combination therapies. Integrating endovascular strategies with innovative chemotherapies and immunotherapies may transform GBM management, but further research is required to establish their efficacy and safety in clinical practice.

Neuroendovascular medicine is moving beyond purely mechanical treatment toward catheter-based systems that also deliver biologic therapies. In this narrative review, “biologic-enabled neurointervention” denotes three groups, distinguished throughout and grouped by route rather than regulatory class: true biologic products (recombinant proteins, monoclonal antibodies, cell therapies, extracellular vesicles and gene-transfer vectors); adjunctive small-molecule pharmacotherapy; and bioengineered device and nanocarrier platforms. We synthesize clinical, translational and preclinical evidence on periprocedural pharmacotherapy, bioactive devices, biologics for delayed cerebral ischemia, genotype-guided and anti-angiogenic therapies for arteriovenous malformations (AVMs), endovascular stem cell delivery, intra-arterial gene therapy and nanoscale delivery platforms. Superselective intra-arterial delivery may achieve higher target-site concentrations, lower systemic exposure and access to difficult-to-reach territories, although these advantages are not universal and depend on cerebral blood flow, first-pass extraction, molecular size and barrier integrity. Limitations include immunogenicity, off-target distribution, procedure-related risk, small and heterogeneous clinical datasets, and unresolved regulatory and manufacturing pathways for living and gene-based products. With the exception of adjunctive intra-arterial thrombolysis, which is supported by randomized evidence, the approaches reviewed here remain predominantly investigational, and each is assigned an explicit evidence tier. Whether biologic-enabled neurointervention becomes an integrated component of standard cerebrovascular care will depend on adequately powered multicenter trials.