Nose-to-brain delivery of transferrin-modified carmustine-loaded iron nanoparticles for enhanced glioblastoma treatment

Glioblastoma multiforme (GBM) treatment is hindered by the blood-brain barrier (BBB) and an immunosuppressive tumour microenvironment (TME) rich in M2 tumor-associated macrophages (TAMs). Carmustine (BCNU) efficacy is limited by systemic toxicity. To address this, we developed transferrin-modified, BCNU-loaded superparamagnetic iron oxide nanoparticles (Tf/BCNU-SPIONs) for nose-to-brain delivery. Optimized Tf/BCNU-SPIONs were monodisperse (41.92 ± 2.81 nm), with high BCNU encapsulation (&gt;80%) and transferrin anchoring (∼98%). Cellular studies showed Tf/BCNU-SPIONs enhanced Gl261 cellular uptake 2.1-fold versus non-targeted nanoparticles, achieving 76.4 ± 6.29% apoptosis at 8 h. In orthotopic GBM mice, single-dose intranasal administration suppressed tumour growth by 84.6 ± 5.3% (<i>p</i> &lt; 0.01 vs. saline) and extended maximum survival to &gt;60 days (vs. 48 days for free BCNU), due to BBB bypass and transferrin targeting. Crucially, SPIONs reprogrammed TAMs in the TME, increasing M1 polarization to 41.8 ± 6.5% (vs. 6.5 ± 3.2% in controls, <i>p</i> &lt; 0.01). Safety assessments showed minimal hepatorenal/hematologic toxicity (<i>p</i> &gt; 0.05 vs. saline) at just 20% of the clinical BCNU dose. This work establishes a synergistic chemo-immunotherapeutic strategy that concurrently overcomes BBB limitations, reprograms the immunosuppressive TME, and mitigates systemic toxicity, demonstrating promising preclinical efficacy.