Chelating Lipids as Polymer-Free Electrostatic Stabilizers for Monoolein-Phospholipid Nanoparticles

Chelator-functionalized lipids can stabilize nonlamellar lipid nanoparticles while introducing metal-binding sites at soft interfaces. Here, we test whether anionic diethylenetriaminepentaacetic acid-phospholipids (DTPA-PEs) and their gadolinium (Gd) complexes can act as polymer-free electrostatic stabilizers for monoolein (MO)-rich nanoparticles in water while embedding metal-binding sites directly at the lipid-water interface. Replacing part of DOPC in MO/DOPC (17:3) mixtures with DTPA-PE (14:0 or 18:0) or Gd-DTPA-PE yields ternary dispersions that remain predominantly nanoscale, whereas MO and MO/DOPC controls coarsen to broad, multimodal distributions with micrometer-scale populations. By systematically varying chelator loading, acyl-chain length, and metal loading and characterizing the resulting dispersions by dynamic light scattering (DLS), polarized light microscopy (PLM), variable-temperature DLS, ζ potential measurements, and solution 1H NMR, we identify a chelator loading window of approximately 10-12.5 mol % in which particles remain in the range of 150-300 nm over time. Within this window, PLM, variable-temperature DLS, and sharp 1H NMR resonances support isotropic, cubic-like, or spongosome-like internal order inferred from these indirect probes rather than simple micelles or lamellar vesicles. ζ potentials of about -25 to -50 mV show that both metal-free and Gd-loaded particles remain strongly anionic, consistent with electrostatic contributions to polymer-free stabilization. These results establish DTPA-type lipids as modular interfacial elements that couple electrostatic stabilization with metal coordination in polymer-free MO-rich nanoparticles, while the mesophase symmetry remains only cubic-like or nonlamellar by inference; definitive assignment will require small-angle X-ray scattering (SAXS).