Chemical Programming of Intratumoral Boron for Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) is a radiotherapeutic modality in which biological selectivity is dictated not by targeting alone but by the spatial control of nuclear reactions. Following tumor-selective accumulation of 10B, neutron irradiation induces the 10B(n,α)7Li reaction, generating high-linear energy transfer particles with micrometer path lengths that confine cytotoxicity to boron-enriched cells. Despite its intrinsic precision, the clinical translation of BNCT has long been hindered by a fundamental chemical challenge: the inability to achieve sufficient, homogeneous, and durable intratumoral boron distribution. In this Account, we argue that BNCT must be reframed as a problem of chemical architecture across length scales, rather than a simple paradigm of boron delivery followed by irradiation. Building on foundational contributions from Jin-Ho Choy (layered double hydroxide-based confinement and ion-exchange systems), Hiroyuki Nakamura (molecular boron design enabling targeting and functional integration), and Koji Ono (clinical dosimetry and translational constraints), we outline how nanohybrid platforms transform BNCT into an integrated systems therapy in which materials design, biological transport, and radiation physics are co-optimized. We identify three governing design principles for next-generation BNCT. First, structural confinement and high-density boron loading enabled by layered inorganic hosts, carborane clusters, and hybrid nanocarriers, ensure sufficient payload delivery at the cellular and subcellular levels. Second, spatiotemporal control of boron distribution, achieved through surface engineering, targeting ligands, and microenvironment-responsive release, addresses the critical challenge of intratumoral heterogeneity. Third, integration with imaging and dosimetry establishes a "measure-what-you-treat" paradigm, linking molecular design directly to therapeutic outcome. We further highlight that BNCT efficacy is governed not by bulk tumor boron concentration alone but by microdistribution and subcellular localization, reflecting the short path length of high-linear energy transfer(LET) particles. This insight shifts design strategies from maximizing systemic delivery toward controlling intracellular fate and spatial precision. In parallel, the transition to accelerator-based neutron sources imposes additional constraints on boron chemistry, necessitating higher delivery efficiency and tighter coordination between pharmacokinetics and irradiation conditions. Together, these advances position BNCT as a chemically programmable precision radiotherapy, in which therapeutic outcome is dictated by the hierarchical organization of boron from molecular to nanoscale to clinical dimensions. Future progress will depend on scalable chemical design, quantitative imaging of boron distribution, and integration with emerging therapeutic modalities. We propose that the next phase of BNCT will be defined by the convergence of nanochemistry, systems-level transport control, and clinically informed design, enabling broader translation into refractory and heterogeneous cancers.