Coupling Adoptive Cell Therapy with Boron Neutron Capture Therapy: Using Functional Tumor-Infiltrating Lymphocytes for Tumor Delivery of Boron Carbide Nanoparticles.

Nanomedicine offers promising strategies for targeted drug delivery, imaging, and molecular-level therapies. However, the clinical translation of nanomedicine has often been hindered by the complex interactions of nanoparticles (NPs) with biological systems. This study investigates a cell-based delivery platform designed to overcome some of these limitations, using clinical-grade tumor-infiltrating lymphocytes (TILs) as biological carriers of boron carbide (B(4)C) NPs in boron neutron capture therapy (BNCT). Biological vectors, such as TILs, could enable selective tumor targeting, leading to highly localized (10)B levels and minimizing off-target accumulation. We evaluated the uptake and retention of composite Fe(2)O(3)-B(4)C NPs (FeBNPs) using both immortalized Jurkat T cells and primary human TILs. Both cell types efficiently internalized FeBNPs without cytotoxic effects, maintained their functionalities, and retained the boron-rich NPs for up to 72 h. Imaging confirmed intracellular localization, and neutron autoradiography demonstrated that TILs accumulated sufficient (10)B for therapeutic efficacy, eliminating the need for isotopically enriched compounds like L-4-boronophenylalanine (BPA) or sodium borocaptate (BSH). Coculture experiments with Jurkat and HeLa cells confirmed that lymphocyte-delivered boron could mediate localized radiation damage via neutron capture. These findings support the concept of TILs as "Trojan Horses" for boron delivery, allowing for overcoming traditional barriers in NP-based therapies and taking advantage of their innate tumor-homing ability. This approach not only enhances BNCT selectivity and efficacy but also supports the integration of nanomedicine with adoptive cell therapy in a combined cancer treatment framework.