Synergistic drug homing for glioblastoma: Integrating biomimetic nanocarriers with MR-guided focused ultrasound across the blood-brain barrier

Background The blood–brain barrier (BBB) and its pathological counterpart, the heterogeneous blood–tumor barrier (BTB), remain major obstacles to effective chemotherapy for glioblastoma multiforme (GBM). Although bioengineered nanocarriers exploiting receptor-mediated transcytosis have shown promise for targeted drug delivery, their efficacy is constrained by receptor saturation, endogenous ligand competition, and endosomal sequestration. Magnetic resonance-guided focused ultrasound (MRgFUS) enables transient and localized BBB opening but lacks intrinsic tumor selectivity. Objective This review aimed to answer the following PICO question: In patients or animal models with GBM (Population ) , does the combination of systemically administered nanocarriers with MRgFUS (Intervention), compared with systemic nanocarriers or FUS alone (Comparison), improve BBB penetration, drug accumulation, or survival outcomes (Outcome)? Methods This systematic review was conducted in accordance with the PRISMA 2020 guidelines. The search strategy combined MeSH and free-text terms: ('blood-brain barrier’ OR BBB) AND ('glioblastoma’ OR GBM) AND ('nanoparticle ’ OR ‘nanocarrier ’ OR ‘exosome ’) AND ('focused ultrasound’ OR 'MRgFUS' OR ‘microbubble ’) in PubMed, Web of Science, and Scopus for articles published January 2018–December 2025. Eligible studies included preclinical or clinical investigations reporting the use of systemically administered nanocarriers combined with focused ultrasound for GBM therapy. Two reviewers independently performed study selection and data extraction . Effect measures extracted included fold changes in brain accumulation (%ID/g or AUC), median survival differences, and tumor volume reductions. Owing to substantial heterogeneity in study designs, nanoparticle platforms, animal models, and outcome measures, a narrative synthesis was performed. Methodological quality was assessed qualitatively; confidence in the synthesized evidence was evaluated using a GRADE-informed approach considering study limitations, inconsistency, indirectness, imprecision, and publication bias. A review protocol was not prospectively registered. Results Of 1247 records identified, 83 studies met the inclusion criteria (80 preclinical, 3 clinical). The evidence supports a Synergistic Drug Homing (SDH) paradigm integrating biomimetic nanocarriers with spatiotemporally controlled acoustic modulation of BBB permeability. Across representative studies, MRgFUS increased intraparenchymal drug accumulation by approximately 2- to 7.7-fold compared with systemic administration alone. Polymeric, lipid-based, biomimetic, and inorganic nanoplatforms demonstrated enhanced brain delivery and antitumor efficacy when combined with ultrasound-mediated opening of the BBB. Critical translational barriers identified included interspecies differences in BBB physiology, the “last-micron” intratumoral delivery challenge, manufacturing scalability, inconsistent reporting standards, and uncertainties regarding long-term neurotoxicity. Overall confidence in the evidence was rated moderate for preclinical outcomes (due to heterogeneity and risk of bias) and low for clinical outcomes (due to small sample sizes and lack of controlled trials). Limitations The available evidence was dominated by heterogeneous preclinical studies with variable methodologies and outcome measures. Direct head-to-head comparisons between combination therapies and monotherapies were limited, precluding quantitative meta-analysis. Publication bias and incomplete reporting may have led to an overestimation of therapeutic efficacy. The review's processes themselves were limited by the lack of a registered protocol and the exclusion of non-English studies. Conclusions The SDH framework provides a cohesive translational roadmap that bridges biomimetic nanomedicine design with externally controlled modulation of the BBB. The convergence of nanocarrier engineering and MRgFUS represents a promising strategy to overcome BBB-associated barriers to GBM therapy. Future progress will require standardized reporting practices, rigorous long-term safety assessment, adaptive theranostic platforms, and artificial intelligence-driven treatment personalization to facilitate clinical translation.