Boron-embedded multifunctional nanoplatform toward potential combined boron neutron capture therapy and immunomodulation in glioma.

Glioma poses a formidable therapeutic challenge due to its cellular heterogeneity, invasiveness and the protective blood-brain barrier (BBB). Boron neutron capture therapy represents a promising binary targeted radiotherapy, but its efficacy is hampered by insufficient tumor-specific accumulation, limited real-time monitoring capabilities of boron agents, and the immunosuppressive tumor microenvironment (TME). Although L-4-boronophenylalanine (BPA) is the only boron agent approved in Japan for Boron neutron capture therapy, its suboptimal tumor specificity and rapid metabolism limit effective accumulation in glioma. In this work, we engineered a theranostic strategy based on a brain-targeting nanoplatform (DM&Ce6@COF-Ang). Boron-embedded APTES-COF-1, with a high intrinsic boron content of 13.5%, served as both a therapeutic boron agent and a nanocarrier to deliver the STING agonist DMXAA (abbreviated as DM) and the fluorescent probe chlorin e6 (Ce6). The targeting ligand Angiopep-2 was utilized to facilitate low-density lipoprotein-related protein-1 (lipoprotein receptor-related protein 1) receptor-mediated transcytosis across the BBB. Specifically, DM@COF-Ang demonstrated superior tumor-specific accumulation in orthotopic glioma-bearing mice, reaching a tumor boron concentration of 11.3 ± 2.9 ppm (natural abundance boron, ∼19.8% 10B) (T/N ≈ 4.0), whereas BPA yielded only 1.9-3.8 ppm (T/N ≈ 2.0). Simultaneously, the nanoplatform selectively delivered DMXAA to glioma, triggering STING pathway activation and reprogramming the immunosuppressive TME. Importantly, the co-delivered Ce6 functioned as a modal imaging agent, enabling accurate tracking of DM@COF-Ang biodistribution and confirming the feasibility of real-time monitoring. This multifunctional nanoplatform achieved synergistic tumor-specific boron delivery, real-time pharmacokinetic monitoring, and immunomodulation. The modular design establishes a versatile foundation for developing personalized, potential BNCT-based combination therapies.