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Although substantial progress has been made in drug development, effective clinical translation is still constrained by inefficient delivery across the blood brain barrier (BBB) and blood brain tumor barrier (BBTB), insufficient tumor accumulation, intratumoral heterogeneity, acquired therapeutic resistance, and dose limiting systemic toxicity. Nanomedicine offers a promising strategy to address these barriers through tunable physicochemical properties, flexible surface functionalization, improved pharmacokinetics, and controllable drug release. In this review, we systematically summarize recent advances in nanomedicine enabled GBM therapy from four interrelated perspectives: the optimization of nanomaterial properties, the development of goal\u2010oriented targeting strategies, the rationalization of delivery routes, and the engineering of smart stimuli\u2010responsive nano\u2010systems. Rather than only cataloguing representative nanoplatforms, we emphasize how material parameters, biological targeting mechanisms, delivery routes, and release behaviors are mechanistically linked to BBB or BBTB penetration, tumor accumulation, therapeutic efficacy, and translational feasibility. Importantly, we also incorporate a key failure case analysis of representative clinical and preclinical studies, highlighting why promising nanotherapeutic concepts may fail because of inadequate intratumoral distribution, insufficient survival benefit, poor patient selection, manufacturing complexity, safety concerns, or impractical trial design. By integrating delivery mechanisms, cross platform comparison, translational barriers, and future optimization principles, this review provides a critical and forward looking framework for the rational design of precise, effective, and clinically translatable nanomedicine strategies for GBM treatment.<\/jats:p>","DOI":"10.1002\/wnan.70071","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:12:58Z","timestamp":1785283978000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Nanomedicine for Glioblastoma Therapy: Novel Insights and Future Perspectives"],"prefix":"10.1002","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0969-5913","authenticated-orcid":false,"given":"Yu","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Neurosurgery Northern Jiangsu People's Hospital Affiliated to Yangzhou University  Yangzhou Jiangsu People's Republic of 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