Mapping Aptamer Prototypes to the Unmet Gaps of Glioblastoma Care: From Circulating Cells to the Resection Cavity

Background: Glioblastoma remains poorly controlled despite maximal safe resection, radiotherapy, and temozolomide. Six problems remain unresolved along this pathway: epithelial-marker-based capture can miss glial cells; infiltration extends beyond visible margins; residual disease survives resection; the blood–brain barrier restricts delivery; receptor switching and stem-like states enable escape; and immune control remains inadequate. This review considers aptamer approaches to these limitations while distinguishing experimental candidates from clinical practice. Methods: This narrative synthesis incorporates PubMed records, supplementary Google Scholar searches, primary experimental and clinical reports, and registry verification. Evidence is distinguished by tumor type, model, route, and endpoint; no meta-analysis was performed. Results: An EpCAM-independent DNA aptamer supports circulating glioma-cell isolation in a small patient series. A near-infrared conjugate labels ex vivo human tissue and animal tumors, but its reported study did not include intraoperative use in patients. Antagonists, photodynamic constructs, and magnetic nanodiscs provide preclinical approaches to tumor-cell control; nanodisc evidence includes separate ascites and glioblastoma studies. Delivery platforms range from receptor-targeted nanoparticles and STAT3 siRNA chimeras to aptamer–drug conjugates selected in orthotopic patient-derived xenografts. Combined receptor blockade and EphA2 targeting address escape experimentally. GLORIA has published phase I/II dose-escalation and bevacizumab-expansion cohorts for the CXCL12-binding L-RNA olaptesed pegol, while a bispecific 4-1BB–osteopontin aptamer provides glioma-specific preclinical immune-directed evidence. Conclusions: Selected studies are relevant to each limitation, but heterogeneous evidence and conceptual selection preclude claims of comprehensive coverage or clinical resolution. Local cavity delivery remains a development hypothesis requiring independent safety and efficacy assessment. Aptamers should complement—not replace—established care.