Polymer-Directed Self-Assembly of BCNO Nanoparticles for Efficient Boron Utilization in Boron Neutron Capture Therapy

Boron carbon oxynitride (BCNO) nanoparticles are attractive boron-rich agents for boron neutron capture therapy (BNCT), yet their polymer-directed self-assembly, structural regulation, and delivery-function relationships remain insufficiently explored. Here, we report a stimuli-responsive polymer-BCNO nanoassembly, mPEG/PS-b-PEI@BCNO, that integrates macromolecular self-assembly with efficient boron utilization for BNCT against pancreatic cancer. The amphiphilic mPEG/PS-b-PEI copolymer was constructed by coupling methoxy poly-(ethylene glycol) (mPEG), polystyrene (PS), and poly-(ethylenimine) (PEI) through acid-labile Schiff-base linkages. Electrostatic complexation between negatively charged BCNO nanoparticles and cationic PEI, combined with solvent-driven amphiphilic assembly, generated spherical nanoassemblies with tunable morphology, size, and surface charge. Systematic variation of the mPEG/PS ratio revealed that the hydrophobic-hydrophilic balance of the copolymer governs BCNO packing and nanoassembly formation. The optimized mPEG/PS-b-PEI@BCNO nanoassemblies exhibited a uniform diameter of approximately 61 nm, positive surface charge, PEG-mediated colloidal stabilization, and acid-triggered disassembly into smaller BCNO-containing fragments under tumor-relevant acidic conditions. Despite a relatively low BCNO content of approximately 8 wt %, mPEG/PS-b-PEI@BCNO markedly improved boron delivery in UN-KC-6141 pancreatic cancer cells; the nanoassemblies achieved higher boron uptake efficiency than bare BCNO and boronophenylalanine (BPA). In 3D pancreatic tumor spheroids, mPEG/PS-b-PEI@BCNO delivered boron concentrations above the therapeutic threshold for BNCT and exhibited boron utilization efficiencies of 16.64% at pH 7.4 and 10.89% at pH 6.5. Under equivalent ¹⁰B dosing, the nanoassemblies produced the strongest BNCT response in 3D spheroids, inducing approximately 52% cell death and significantly outperforming bare BCNO and BPA. These findings demonstrate that polymer-controlled nanoassembly architecture enhances boron utilization without relying solely on high intrinsic boron loading, establishing a design framework for the next-generation BNCT nanodrugs.