MOF-Based Arginine Nanocarriers for Coordinated Immunometabolic and Antitumor Modulation in Triple Negative Breast Cancer

Abstract

L-arginine (L-Arg) is a key immunometabolite and nitric oxide (●NO) precursor with therapeutic potential in cancer and immunotherapy. However, its clinical application is hindered by poor bioavailability and uncontrolled dosing. Here, two distinct metal–organic frameworks (MOFs), NH₂-MIL-125(Ti) and MOF-808(Zr), were designed as nanocarriers for Arg to coordinate immunometabolic reprogramming and gasotransmitter-mediated cytotoxicity in triple-negative breast cancer (TNBC). L-Arg loading and release were characterized, followed by Seahorse metabolic flux, flow cytometry, live-cell imaging, and wound healing assays to evaluate the impact on activated human T cells and iNOS-transduced MDA-MB-231 cells. Comprehensive physicochemical characterization confirmed successful L-Arg loading and distinct release kinetics. In activated CD4⁺ T cells, MOF-808-Arg enhanced oxidative phosphorylation and preserved spare respiratory capacity, while NH₂-MIL-125-Arg triggered hypermetabolism and proton leak, mimicking high-dose L-Arg stress. In iNOS-expressing MDA-MB-231 cells, both MOFs increased intracellular ●NO levels, suppressed viability, and inhibited migration. These findings highlight the importance of controlled arginine kinetics and demonstrate that MOF-808-Arg offers a metabolically favourable and immunostimulatory profile. This work introduces MOF-based nutrient delivery as a versatile strategy for simultaneous immune and tumour modulation in metabolically hostile cancers like TNBC.