Boron Neutron Capture Therapy at a Crossroads: Translational Gap and Emerging Delivery Agents

Boron neutron capture therapy (BNCT) combines molecular targeting with localized high linear energy transfer radiation, offering a highly selective treatment for refractory malignancies. Despite decades of research, all clinical BNCT trials to date have relied exclusively on the legacy agents boronophenylalanine (BPA) and sodium borocaptate (BSH), reflecting historical precedent and regulatory familiarity rather than optimal pharmacological performance. Recent advances in boron chemistry, nanotechnology, and molecular imaging have generated a new generation of boron delivery agents with improved tumor selectivity, multifunctionality, and theranostic potential, yet none have reached clinical translation. This review covers boron carriers reported since 2018, categorized as small molecules, boronated polymers and liposomes, boron-conjugated biomolecules, and imaging-guided or theranostic systems. Trends derived from bibliometric analysis reveal a shift toward nanoparticle-based carriers, which offer modular architectures for simultaneous drug loading, targeting, and imaging. Among these, multifunctional nanoplatforms appear particularly promising for personalized BNCT, where in vivo imaging via PET, MRI, SPECT, or fluorescence can enable patient-specific treatment planning and real-time dosimetry. However, the translation of these innovative agents remains constrained by economic, regulatory, and logistical barriers. The field's next frontier will require harmonized dosimetry protocols, validated imaging standards, and coordinated industrial and academic investment to bridge the gap between chemistry and clinic. BNCT thus stands at a translational gap: sustained interdisciplinary collaboration could finally expand its clinical repertoire beyond BPA and BSH toward a new generation of targeted and image-guided boron therapeutics.