Farah Benyettou, Thirumurugan Prakasam, Mostafa Khair, Osama Abdullah, Matteo Lusi, Haidee Paterson, Maryam Alkaabi, Sneha Thomas, Rainer Straubinger, Nosayba Al Damook, Maylis Boitet, Mamoun Abelbaki, J. Del Monte, Diana Yu, Rick Heinz, Sheri L. Holmen, Edward W. Hsu, Carlos Platas-Iglesias, Gennaro Esposito, Ali Trabolsi
High Resolution Image Download MS PowerPoint Slide Manganese (Mn)-based metal–organic architectures offer a unique avenue for integrating magnetic resonance imaging (MRI) and cancer therapy within a single molecular platform. We report three topologically distinct Mn-templated structures─Mn-[2]Catenate (Mn-[2]C), Mn-Trefoil Knot (Mn-TK), and Mn-Borromean Rings (Mn-BR)─that combine high relaxivity with tumor-selective cytotoxicity. The design leverages their geometrical complexity and electropositive, pH-labile coordination framework to ensure kinetic stability and lipophilicity at physiological pH while enabling Mn 2+ release in the acidic tumor microenvironment. Among the three, Mn-BR and Mn-TK exhibit superior longitudinal relaxivities ( r 1 = 10.1 and 6.8 mM –1 .s –1 at 3 T) and produce bright T 1 -weighted contrast exceeding that of Gd-DTPA and Mn-DPDP. In vitro, they show high cancer selectivity and potency in glioblastoma (U251-MG) cells, with IC 50 values of 3.0 ± 0.9 μM (Mn-BR) and 5.6 ± 1.9 μM (Mn-TK), outperforming cisplatin (12.7 ± 2.5 μM) while sparing normal cells (SI > 3.9 for Mn-TK; SI > 9.4 for Mn-BR). Mechanistically, their uptake proceeds via energy-dependent endocytosis─caveolae-mediated for Mn-TK and clathrin/macropinocytosis-driven for Mn-BR─culminating in lysosomal acidification, pH-triggered disassembly, Mn 2+ release, ROS accumulation, and caspase-dependent apoptosis. In vivo, Mn-TK and Mn-BR achieve tumor-specific accumulation, strong MRI contrast, and pronounced growth inhibition in subcutaneous glioblastoma models, while Mn-[2]C shows minimal selectivity and higher systemic toxicity. Importantly, in a spontaneous orthotopic glioblastoma model, both Mn-TK and Mn-BR provided robust BBB permeability and persistent, tumor-specific MRI enhancement, confirming their potential for precise MRI-guided tumor visualization. This research marks a major leap forward in medical nanotechnology, unveiling a new class of metal–organic structures that seamlessly integrates imaging and therapy. By unlocking their full potential, these structures promise to revolutionize MRI diagnostics, precision medicine, and next-generation cancer treatments, paving the way for unparalleled clinical outcomes.