Emerging agents for boron neutron capture therapy: Biomolecular carriers paving the way for precision radiotherapy

Boron neutron capture therapy (BNCT) is an emerging targeted radiotherapy technology that enables precise eradication of tumor cells. The development of efficient boron carriers is crucial for the advancement of BNCT technology. Notably, biomolecular carriers currently represent the only class of drug carriers that has achieved market approval (e.g., boronophenylalanine [BPA] in Japan), underscoring their pivotal role in clinical applications. Their outstanding biocompatibility, high payload capacity, and tumor-targeting capabilities align closely with the stringent requirements of BNCT drug delivery. For instance, amino acid-based carriers (such as BPA) utilize L-type amino acid transporter 1 (LAT1) for tumor-specific accumulation; nucleoside prodrugs are activated by thymidine kinase 1 (TK1) and incorporated into tumor DNA; carbohydrate-based carriers improve solubility and targeting through glucose transporters (GLUTs); peptide carriers facilitate cellular uptake via receptor-mediated endocytosis or cell-penetrating peptides; and liposomes leverage the enhanced permeability and retention (EPR) effect together with active-targeting modifications for enhanced tumor delivery. Nevertheless, delivering ultrahigh doses of boron remains a major challenge. Biomacromolecules, particularly albumin-based systems, have garnered increasing attention because of their excellent biosafety and high boron-loading potential, offering promising avenues for overcoming dose delivery barriers in BNCT. This review systematically summarizes the recent advances in biomolecular carriers for BNCT and highlights emerging applications of protein-based boron carriers, addressing a notable gap in the comprehensive review of biomolecular strategies within the BNCT drug delivery field.