Manganese-Templated Nontrivial Structures for MRI and Therapy

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 Mn²⁺ release in the acidic tumor microenvironment. Among the three, Mn-BR and Mn-TK exhibit superior longitudinal relaxivities (<i>r</i>₁ = 10.1 and 6.8 mM^-1.s^-1 at 3 T) and produce bright <i>T</i>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 IC₅₀ 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, Mn²⁺ 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.