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.