Concentration-Responsive Gd–DOTA Nanomicelles via Chain-Length Engineering for Transporter-Independent Hepatobiliary Magnetic Resonance Imaging

Balancing the thermodynamic stability and biological clearance of supramolecular assemblies represents a fundamental challenge in the design of functional nanomedicines. To address this, we propose a concentration-responsive “assemble-for-uptake, disassemble-for-clearance” strategy implemented via rational molecular engineering of a minimalist, single-component Gd–DOTA amphiphile. We demonstrate that the alkyl chain length acts as a precise molecular dial to tune the critical micelle concentration (CMC), thereby dictating micellar stability, biological identity, and clearance pathways. Through this tuning, we identified Gd–C12 as the optimized agent, which self-assembles into spherical nanomicelles (38.6 ± 8.3 nm) with desirable T1 contrast (r2/r1 < 2) and kinetic stability surpassing unmodified Gd–DOTA. In vivo studies reveal that Gd–C12 provides potent hepatic enhancement (120% increase) via favorable MPS recognition, independent of organic anion-transporting polypeptide (OATP). Crucially, following hepatic uptake, the agent undergoes spontaneous disassembly upon physiological dilution/excretion, facilitating rapid systemic clearance (>97%) to resolve long-term retention concerns. This work presents Gd–C12 as a high-performance, transporter-independent contrast agent that bridges the gap between nanoparticles and small molecules, holding promise for providing reliable hepatic parenchymal enhancement regardless of OATP expression levels.