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Protein-polyelectrolyte complex coacervation is of particular interest for mimicking intracellular phase separation and organization. Yet, the challenge arises from regulating the coacervation due to the globular structure and anisotropic distributed charges of protein. Herein, we fully investigate the different control factors and reveal their effects on protein-polyelectrolyte coacervation. We prepared mixtures of BSA (bovine serum albumin) with different cationic polymers, which include linear and branched polyelectrolytes covering different spacer and charge groups, chain lengths, and polymer structures. With BSA-PDMAEMA [poly(N,N-dimethylaminomethyl methacrylate)] as the main investigated pair, we find that the moderate pH and ionic strength are essential for the adequate electrostatic interaction and formation of coacervate droplets. For most BSA-polymer mixtures, excess polyelectrolytes are required to achieve the full complexation, as evidenced by the deviated optimal charge mixing ratios from the charge stoichiometry. Polymers with longer chains or primary amine groups and a branched structure endow a strong electrostatic interaction with BSA and cause a bigger charge ratio deviation associated with the formation of solid-like coacervate complexes. Nevertheless, both the liquid- and solid-like coacervates hardly interrupt the BSA structure and activity, indicating the safe encapsulation of proteins by the coacervation with polyelectrolytes. Our study validates the crucial control of the diverse factors in regulating protein-polyelectrolyte coacervation, and the revealed principles shall be instructive for establishing other protein-based coacervations and boosting their potential applications.
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Polímeros , Soroalbumina Bovina , Polieletrólitos/química , Soroalbumina Bovina/química , Polímeros/química , Concentração OsmolarRESUMO
Proteins used as building blocks to template nanostructures with manifold morphologies have been widely reported. Understanding their self-assembly and reassembly mechanism is important for designing functional biomaterials. Herein, we show that enzyme-hydrolyzed α-lactalbumin (α-lac) can self-assemble into either nanotubes in the presence of Ca2+ ions or nanospheres in the absence of Ca2+ in solution. Remarkably, such assembled α-lac nanotubes can be elongated by adding preassembled α-lac nanospheres and Ca2+ solution, which suggests that the self-assembled α-lac nanospheres undergo disassembly and reassembly processes into existing nanotube nuclei. By performing atomic force microscopy (AFM), transmission electron microscopy (TEM), and confocal laser scanning microscopy (CLSM), it indicates that there is an equilibrium among nanotubes, nanospheres, hydrolyzed α-lac, and Ca2+ in solution. The structural transition between nanotubes and nanospheres is driven from a less stable structure into a more stable structure determined by the conditions. During the transition from nanospheres into nanotubes, the hydrolyzed α-lac in nanospheres transfers into helical ribbon form at both nanotube extremities. Then helical ribbons close into mature nanotubes, extending the length of the initial nuclei. Besides, by dilution or adding ethylene glycol bis(2-aminoethyl ether) tetraacetic acid (EGTA), the decreased Ca2+ concentration in solution drives the Ca2+ dissociating from nanotubes into solution, leading to the transitions from nanotubes into nanospheres. The reversible transformation between nanotubes and nanospheres is achieved by adjusting the pH value from 7.5 to 5.0 and back to 7.5. This is because the stability of nanotubes decreases from pH 7.5 to 5 but increases from 5 to 7.5. Significantly, this approach can be used for the fabrication of various responsive nanomaterials from the same starting material.
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Nanosferas , Nanoestruturas , Nanotubos , Íons , Materiais BiocompatíveisRESUMO
Achieving organized assembly structures with high complexity and adjustable functionalities is a central quest in supramolecular chemistry. In this report, we study what happens when a discotic benzene-1,3,5-tricarboxamide (BTA) ligand containing three dipicolinic acid (DPA) groups is allowed to coordinate with lanthanide (Ln) ions. A multi-BTA coordination cluster forms, which behaves as a type of "supramolecular monomer", stacking into fibers via hydrogen bonds enabled by multiple BTA cores. The fibrous morphology and size, as well as the packing unit and the process by which it grows, were investigated by light scattering measurements, luminescence spectra, TEM images and molecular simulation data. More notably, by selecting the kind of lanthanide or mixture of lanthanides that is incorporated, tunable luminescence and magnetic relaxation properties without compromising the fibrous structure can be realized. This case of hierarchical self-assembly is made possible by the special structure of our BTA-like building block, which makes non-covalent bond types that are different along the radial (coordination bonds) and axial (H-bonds) directions, respectively, each with just the right strength. Moreover, the use of lanthanide coordination leads to materials with metal-derived optical and magnetic properties. Therefore, the established approach demonstrates a novel strategy for designing and fabrication of multi-functional supramolecular materials.
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Zwitterionic polyelectrolyte nanogels are prospective nanocarriers due to their soft loading pocket and regulated charges. We here report a facile strategy, namely, electrostatic-templated polymerization (ETP) for synthesizing zwitterionic nanogels with controlled size and properties. Specifically, with anionic-neutral diblock polymers as the template, zwitterionic monomers such as carboxybetaine methacrylate (CBMA) or carboxybetaine acrylamide (CBAA) are polymerized together with a cross-linker at pH 2 where the monomers exhibit only positive charge due to the protonation of the carboxyl group. The obtained polyelectrolyte complex micelles dissociate upon introducing a concentrated salt. The subsequent separation yields the released template and zwitterionic nanogels with regulated size and swelling ability, achieved by tuning the salt concentration and cross-linker fraction during polymerization. The obtained PCBMA nanogels exhibit charges depending on the pH, which enables not only the selective loading of different dye molecules, but also encapsulation and intracellular delivery of cytochrome c protein. Our study develops a facile and robust way for fabricating zwitterionic nanogels and validates their potential applications as promising nanocarriers for load and delivery of functional charged cargos.
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Uniting photothermal therapy (PTT) with magnetic resonance imaging (MRI) holds great potential in nanotheranostics. However, the extensively utilized hydrophobicity-driven assembling strategy not only restricts the intramolecular motion-induced PTT, but also blocks the interactions between MR agents and water. Herein, we report an aggregation-induced emission luminogen (AIEgen)-mediated polyelectrolyte nanoassemblies (APN) strategy, which bestows a unique "soft" inner microenvironment with good water permeability. Femtosecond transient spectra verify that APN well activates intramolecular motion from the twisted intramolecular charge transfer process. This de novo APN strategy uniting synergistically three factors (rotational motion, local motion, and hydration number) brings out high MR relaxivity. For the first time, APN strategy has successfully modulated both intramolecular motion and magnetic relaxivity, achieving fluorescence lifetime imaging of tumor spheroids and spatio-temporal MRI-guided high-efficient PTT.
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Corantes Fluorescentes , Imageamento por Ressonância Magnética , Polieletrólitos , ÁguaRESUMO
Polyelectrolyte nanogels containing cross-linked ionic polymer networks feature both soft environment and intrinsic charges which are of great potential for enzyme encapsulation. In this work, well-defined poly(acrylic acid) (PAA) nanogels have been synthesized based on a facile strategy, namely, electrostatic assembly directed polymerization (EADP). Specifically, AA monomers are polymerized together with a cross-linker in the presence of a cationic-neutral diblock copolymer as the template. Effects of control factors including pH, salt concentration, and cross-linking degree have been investigated systematically, based on which the optimal preparation of PAA nanogels has been established. The obtained nanogel features not only compatible pocket for safely loading enzymes without disturbing their structures, but also abundant negative charges which enable selective and efficient encapsulation of cationic enzymes. The loading capacities of PAA nanogels for cytochrome (cyt c) and lysozyme are 100 and 125 µg/mg (enzyme/nanogel), respectively. More notably, the PAA network seems to modulate a favorable microenvironment for cyt c and induces 2-fold enhanced activity for the encapsulated enzymes, as indicated by the steady-state kinetic assay. Our study reveals the control factors of EADP for optimal synthesis of anionic nanogels and validates their distinctive advances with respect to efficient loading and activation of cationic enzymes.
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Polietilenoglicóis , Polímeros , Nanogéis , Polieletrólitos , Polietilenoglicóis/química , Polimerização , Eletricidade EstáticaRESUMO
Associations of amphiphiles assume their various morphologies according to the so-called packing parameter under thermodynamic control. However, one may raise the question of whether polymers can always relax fast enough to obey thermodynamic control, and how this may be checked. Here, a case of polyion complex (PIC) assemblies where the morphology appears to be subject to kinetic control is discussed. Poly (ethylene oxide)-b-(styrene sulfonate) block copolymers are combined with cationic PAMAM dendrimers of various generations (2-7). The PEO-PSS diblocks, and the corresponding PSS-PEO-PSS triblocks should have nearly identical packing parameters, but surprisingly creat different assemblies, namely core-shell micelles and vesicles, respectively. Moreover, the micelles are very stable against added salt, whereas the vesicles are not only much more sensitive to added salt, but also appear to exchange matter on relevant time scales. The small and largely quenched early-stage precursor complexes are responsible for the morphological and dynamic differences, implying that kinetic control may also be a way to obtain particles with well-defined and useful properties. The exciting new finding that triblocks produce more "active" vesicles will hopefully trigger the exploration of more pathways, and so learn how to tune PICsomes toward specific applications.
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Dendrímeros , Cátions , Micelas , Polietilenoglicóis , PolímerosRESUMO
Polyelectrolyte (PE) nanogels consisting of cross-linked PE networks integrate the advanced features of both nanogels and PEs. The soft environment and abundant intrinsic charges are of special interest for enzyme immobilization. However, the crucial factors that regulate enzyme encapsulation and activation remain obscure to date. Herein, we synthesized cationic poly (dimethyl aminoethyl methacrylate), PDMAEMA, nanogels with well-defined size and cross-link degrees and fully investigated the effects of different control factors on lipase immobilization. We demonstrate that the cationic PDMAEMA nanogels indeed enable efficient and safe loading of anionic lipase without disturbing their structures. Strong charge interaction achieved by tuning pH and larger particle size are favorable for lipase loading, while the enhanced enzymatic activity demands nanogels with smaller size and a moderate cross-link degree. As such, PDMAEMA nanogels with a hydrodynamic radius of 35 nm and 30% cross-linker fraction display the optimal catalytic efficiency, which is fourfold of that of free lipase. Moreover, the immobilization endows enhanced enzymatic activity in a broad scope of pH, ionic strength, and temperature, demonstrating effective protection and activation of lipase by the designed nanogels. Our study validates the crucial controls of the size and structure of PE nanogels on enzyme encapsulation and activation, and the revealed findings shall be helpful for designing functional PE nanogels and boosting their applications for enzyme immobilization.
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Enzimas Imobilizadas , Lipase , Concentração de Íons de Hidrogênio , Nanogéis , Tamanho da Partícula , PolieletrólitosRESUMO
Polyelectrolyte (PE) nanogels which combine features of nanogels and polyelectrolytes have attracted significant attention as outstanding nano-carriers. However, and crucially, any large-scale application of PE nanogels can only materialize when an efficient production method is available. We recently developed such a robust approach, namely Electrostatic Assembly Directed Polymerization (EADP), in which ionic monomers are polymerized together with cross-linker in the presence of a polyion-neutral diblock copolymer as template. Although EADP achieves efficient and scalable preparation of diverse PE nanogels, the essential factors for the optimal and controlled synthesis of nanogels have remained elusive. In this article, we investigate systematically the effects of pH, salt concentration, and cross-linker fractions on the formation and properties of a PDMAEMA nanogel prepared with PAA-b-PEO as the template. We find that the electrostatic interaction between the building blocks is crucial to obtain assembly-controlled polymerization, and we establish preferred pH, salt concentration and cross-linker fractions. The obtained PDMAEMA nanogel exhibits dual-responses to pH and salt, which allow manipulation of the positive charges of the nanogels for selective loading and controlled release of anionic substances; we demonstrate this with an anionic dye. The study presented here fully addresses the process parameters of EADP regarding optimal and controlled preparation of PE nanogels, which should allow exploration of their potential vis-a-vis a variety of applications.
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Virus-like particles are of special interest as functional delivery vehicles in a variety of fields ranging from nanomedicine to materials science. Controlled formation of virus-like particles relies on manipulating the assembly of the viral coat proteins. Herein, we report a new assembly system based on a triblock polypolypeptide C4-S10-BK12 and -COONa terminated PAMAM dendrimers. The polypolypeptide has a cationic BK12 block with 12 lysines; its binding with anionic PAMAM triggers the folding of the peptide's middle silk-like block and leads to formation of virus-like nanorods, stabilized against aggregation by the long hydrophilic "C" block of the polypeptide. Varying the dendrimer/polypeptide mixing ratio hardly influences the structure and size of the nanorod. However, increasing the dendrimer generation, that is, increasing the dendrimer size results in increased particle length and height, without affecting the width of the nanorod. The branched structure and well-defined size of the dendrimers allows delicate control of the particle size; it is impossible to achieve similar control over assembly of the polypeptide with linear polyelectrolyte as template. In conclusion, we report a novel protein assembling system with properties resembling a viral coat; the findings may therefore be helpful for designing functional virus-like particles like vaccines.
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Dendrímeros , Interações Hidrofóbicas e Hidrofílicas , Nanomedicina , Tamanho da PartículaRESUMO
Polyelectrolyte complex nanoparticles with integrated advances of coacervate complexes and nanomaterials have attracted considerable attention as soft templates and functional nano-carriers. Herein, a facile and robust strategy, namely electrostatic assembly directed polymerization (EADP), for efficient and scalable preparation of stable coacervate nanoparticles is presented. With homo-polyelectrolyte PAA (polyacrylic acid) as template and out of charge stoichiometry, the cationic monomers are polymerized together with cross-linkers, which creates coacervate nanoparticles featuring high stability against salt through one-pot synthesis. The particle size can be tuned by varying the cross-linker amount and salt concentrations during the polymerization and the composition of nanoparticles, as well as the corresponding properties can be regulated by combining different charged blocks from both strong and weak ionic monomers. The strategy can tolerate both high monomer concentrations and increased volume of up to l L, which is favorable for scaled-up preparations. Moreover, the coacervate nanoparticles can be freeze-dried to produce a product in powder form, which can be redispersed without any effect on the particle size and size distribution. Finally, the obtained nanoparticles loaded with enzyme and Au nanoparticles exhibit enhanced catalytic performance, demonstrating a great potential for exploring various applications of coacervate particles as soft and functional nano-carriers.
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Nanopartículas Metálicas , Nanopartículas , Polieletrólitos , Ouro , Polimerização , Eletricidade EstáticaRESUMO
Dendrimer-based PIC micelles are novel nanostructures from the assembly of dendrimers with polyion-neutral diblock copolymers. Because of the branched and three-dimensional structure of dendrimers, understanding the electrostatic assembly is challenging yet essential for manipulating the formation and property of the PIC micelles. Herein, we present the pH effects on the assembly of amine-terminated PAMAM dendrimers with PSS92-b-PEO113 diblock copolymers. The step-wise protonation of primary and tertiary amine groups of PAMAM allows us to manipulate the number of the positive charges by tuning pH. We find that the assembly based on the surface charges of PAMAM from G2 to G7 at pH 7 leads to well-defined micelles with high stability against salt. At pH 3, both the interior and surface charges contribute to the assembly, and the formed micelles are sensitive to ionic strength, namely, increasing salt concentration results in the formation of elongated (G2-G5) or bigger (G7) aggregates. Our study reveals the pH manipulation on the assembly of PAMAM dendrimers with linear polyelectrolytes and displays new findings that shall be helpful for understanding the assembly of asymmetric polyelectrolytes, as well as for designing new PIC micelles and functional soft nanocarriers.
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Core-shell-corona (CSC) micelles have multiple layers, which can serve as separate compartments. This property allows them to combine multiple functionalities in a single nanoparticle, with obvious application potential. Here, we propose a new type of CSC micelles with an apolar core and a polyelectrolyte complex shell incorporating coordination polymers. We obtain these particles by using a poly(styrene)-b-poly(vinyl pyridine)-b-poly(ethylene oxide) (PS-b-PVP-b-PEO) triblock copolymer with quaternized PVP blocks. This polymer leads to well-defined CSC micelles with a cationic shell, which allows us to entrap anionic coordination polymers without disturbing the micellar structure. Useful properties can be imported in this way, e.g., europium (Eu)-based coordination polymers endow the CSC micelles with strong luminescence. Moreover, copper ions (Cu2+) can quench the luminescence because they disturb the Eu-ligand coordination. Upon adding sulfide ions (S2-), copper ions precipitate as CuS and the Eu-ligand bond as well as the corresponding luminescence are restored. This effect is highly specific for Cu2+ and S2-: other cations or anions hardly interfere with this "on-off-on" luminescence response towards Cu2+ and S2-, demonstrating the selectivity of these CSC micelles as detectors of copper and sulfide ions.
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Polyelectrolyte complex based micelles have attracted significant attention due to their potential regarding bio-applications. Although the morphology and functions have been studied extensively, dynamic properties, particularly component exchange with other surrounding molecules, have remained elusive to date. Here, we show how micelles based on metal-ligand coordination complex coacervate-core micelles (M-C3Ms) respond to addition of extra ligand and metal ions. The micelles are prepared from a polycationic-neutral diblock copolymer and an anionic coordination polyelectrolyte, which is obtained by coordination between metal ions (lanthanides Ln3+ and Zn2+) and a bis-ligand (LEO) containing two dipicolinic acid (DPA) groups connected by a tetra-ethylene oxide spacer (4EO). Our findings show that the bis-ligand LEO is essential for the growth of coordination polymers and consequently the formation of micelles, leading to equilibrium structures with the same micellar composition and structure independent of the order of mixing. In other words, adding single DPA has no effect on the formed M-C3Ms. As for metal exchange, we find that added Zn2+ can replace some of the Ln3+ from Ln-C3Ms, leading to a hybrid coordination structure with both Ln3+ and Zn2+. We find that component exchange occurs in these coordination polyelectrolyte micelles, but it is more favorable in the direction of replacing the weak binding components with strong ones. Hence, the designed M-C3Ms based on the strong binding components, such as Ln-C3Ms, shall be relatively stable in biological surroundings, paving the way for the application of such particles as bio-imaging probes.
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Complexos de Coordenação/química , Elementos da Série dos Lantanídeos/química , Polieletrólitos/química , Polímeros/química , Zinco/química , Ligantes , Micelas , Ácidos Picolínicos/químicaRESUMO
We present a simple way to build up well-controlled coacervate-core dendrimicelles by assembly of anionic PAMAM dendrimers with a cationic-neutral diblock copolymer. Upon increasing pH, the formation of micellar structures shows constant size but the number of dendrimer molecules incorporated in one micelle decreases, following the charge stoichiometry formation rules; concomitantly, the salt stability increases. This study shows the straightforward tuning of macromolecular core-units and related micelle properties.
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The stability of polyion complex (PIC) nanoparticles, like PIC micelles or PICsomes, in water is typically affected by added salt because salt screens the electrostatic driving force. This lack of salt stability seriously hampers numerous potential applications and a remedy is needed. Extending an earlier idea, we develop here a general strategy for preparing PIC micelles, with not only tuneable salt stability but also built-in functions. Using two different dipicolinic (DPA)-based ligands (a linear bis-ligand and a branched tris-ligand), as well as various metal ions we obtain anionic coordination polymers that subsequently co-assemble with a polycationic-neutral diblock copolymer to form PIC micelles. By a judicious choice of the metal ions and/or an appropriate mixture of the ligands we can create micellar cores with two types of reversible cross-links. In this way, we construct PIC micelles with not only tuneable and enhanced salt stability, but also tuned metal-derived properties, such as luminescence or magnetic relaxation. This non-covalent cross-link strategy, exclusively based on building block composition, is generally applicable with different metal ions and ligand combinations, and is therefore a robust approach for preparing stable and functional PIC micelles. Extension to other types of assemblies such as 'PICsomes' is possible, and therefore a range of applications becomes feasible.
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Reported here is a new class of PICsomes (vesicles formed by polyelectrolyte complexation) in which the anionic/neutral diblock copolymer is replaced by an anionic, reversible, supramolecular polyelectrolyte based on metal-ligand coordination. This supramolecular polyelectrolyte forms exclusively inside the wall of the assembly, and therefore self-adjusts its length to that of the cationic block provided. Moreover, the supramolecular coordination polyelectrolytes introduce new and tunable properties and functions associated with the specific metal. As a proof-of-concept Mn-based PICsomes were prepared and display high magnetic relaxivity, as well as enhanced contrast in in vitro magnetic resonance imaging tests. The simplicity of our approach, together with the new functions derived from the metal ions, demonstrates a robust strategy for the preparation of a variety of PICsomes with well-defined and tunable structures and properties.
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The ß roll molecules with sequence (GAGAGAGQ)10 stack via hydrogen bonding to form fibrils which have been themselves been used to make viral capsids of DNA strands, supramolecular nanotapes and pH-responsive gels. Accelerated molecular dynamics (aMD) simulations are used to investigate the unfolding of a stack of two ß roll molecules, (GAGAGAGQ)10, to shed light on the folding mechanism by which silk-inspired polypeptides form fibrils and to identify the dominant forces that keep the silk-inspired polypeptide in a ß roll configuration. Our study shows that a molecule in a stack of two ß roll molecules unfolds in a step-wise fashion mainly from the C terminal. The bottom template is found to play an important role in stabilizing the ß roll structure of the molecule on top by strengthening the hydrogen bonds in the layer that it contacts. Vertical hydrogen bonds within the ß roll structure are considerably weaker than lateral hydrogen bonds, signifying the importance of lateral hydrogen bonds in stabilizing the ß roll structure. Finally, an intermediate structure was found containing a ß hairpin and an anti-parallel ß sheet consisting of strands from the top and bottom molecules, revealing the self-healing ability of the ß roll stack.
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Modelos Químicos , Simulação de Dinâmica Molecular , Peptídeos/química , Dobramento de Proteína , Seda/química , Seda/ultraestrutura , Conformação Proteica , Domínios Proteicos , Desdobramento de ProteínaRESUMO
We report a facile and generic method for the synthesis of hollow mesoporous silica nanoreactors (HMSNs) with small-sized metal oxide nanoparticles (NPs) inside their cavities. They were made by deposition of silica onto metal-containing charge-driven polymer micelles and subsequent calcination. The micelles consist of 1)â negatively charged supramolecular polyelectrolyte chains of bis-ligand-bound metal ions, and 2)â water-soluble, neutral/positive diblock copolymers. Owing to the facile coordination between transition-metal ion and the employed bidentate ligand, a series of HMSNs with <2â nm Mx Oy NPs inside cavities (M=Mn, Co, Ni, Cu, or Zn) were obtained by simply varying the metal ions inside the micelles. The developed method circumvents the pre- and post-synthesis of metal oxide NPs; after calcination, hollow mesoporous nanostructures containing small-sized metal oxide NPs inside their cavities are directly obtained. The Cox Oy -functionalized HMSNs catalyze the degradation of various dyes with H2 O2 .
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Three-component mixtures (diblock copolymer/metal ion/oligoligand) can assemble into micellar particles owing to a combination of supramolecular polymerization and electrostatic complex formation. Such particles cover a large range of compositions, but the electrostatic forces keeping them together make them rather susceptible to disintegration by added salt. Now it is shown how the salt stability can be tuned continuously by employing both a bis-ligand and a tris-ligand, and varying the ratio of these in the mixture. For magnetic ions such as MnII and FeIII , the choice of the multiligand also affects the ion/water interaction and, hence, the magnetic relaxivity. As an example, MnII -based nanoparticles with a very high longitudinal relaxivity (10.8â mm-1 s-1 ) were investigated that are not only biocompatible but also feature strong contrast enhancement in target organs (liver, kidney), as shown by T1 -weighted inâ vivo magnetic resonance imaging (MRI).