Biomimetic Macrophage Cell Membrane-Based Nanoparticles for Effective Treatment of Glioblastoma Through Boron Neutron Capture Therapy Combined With Immunotherapy.

Glioblastoma multiforme (GBM) remains largely incurable due to the blood-brain barrier (BBB) and immunosuppressive microenvironment. While boron neutron capture therapy (BNCT) selectively eradicates tumor cells via 10B(n, α)-7Li reactions, its clinical potential in GBM is unrealized because of the suboptimal pharmacokinetics of conventional boron agents and their failure to achieve therapeutic intracranial concentrations. Here, we design macrophage membrane-coated PLGA nanoparticles (M@PLGA-10BN) that exploit innate biological transport mechanisms to overcome dual therapeutic barriers. The macrophage membrane enables: (i) α4β1 integrin-mediated BBB transmigration via VCAM-1 binding, (ii) chemokine-directed tumor tropism, and (iii) CD47-dependent immune evasion. In orthotopic GL261 gliomas, M@PLGA-10BN delivers 53.15 µg/g 10B to tumors - 3.09-fold higher than uncoated nanoparticles - with tumor-to-normal/brain (T/N) and tumor-to-blood (T/B) ratios of 3.95 and 3.85, respectively. Neutron irradiation extends survival by 50 days and triggers immunogenic cell death, increasing tumor-infiltrating CD8+ T cells 4.2-fold while reducing regulatory T cells (Tregs) by 68%. Crucially, BNCT-induced PD-L1 upregulation provides a mechanistic basis for combining with anti-PD-1 immunotherapy, achieving complete tumor regression in 50% of mice. By concurrently overcoming the blood-brain barrier and immunosuppression, this biomimetic strategy unlocks new clinical horizons for BNCT, establishing a new paradigm for treating CNS malignancies.