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. 2023 Nov 6;62(45):e202312925.
doi: 10.1002/anie.202312925. Epub 2023 Oct 6.

Direct Assembly of Metal-Phenolic Network Nanoparticles for Biomedical Applications

Wanjun Xu  1 , Zhixing Lin  1 , Shuaijun Pan  1   2 , Jingqu Chen  1 , Tianzheng Wang  1 , Christina Cortez-Jugo  1 , Frank Caruso  1
Affiliations

Direct Assembly of Metal-Phenolic Network Nanoparticles for Biomedical Applications

Wanjun Xu et al. Angew Chem Int Ed Engl. .

Abstract

Coordination assembly offers a versatile means to developing advanced materials for various applications. However, current strategies for assembling metal-organic networks into nanoparticles (NPs) often face challenges such as the use of toxic organic solvents, cytotoxicity because of synthetic organic ligands, and complex synthesis procedures. Herein, we directly assemble metal-organic networks into NPs using metal ions and polyphenols (i.e., metal-phenolic networks (MPNs)) in aqueous solutions without templating or seeding agents. We demonstrate the role of buffers (e.g., phosphate buffer) in governing NP formation and the engineering of the NP physicochemical properties (e.g., tunable sizes from 50 to 270 nm) by altering the assembly conditions. A library of MPN NPs is prepared using natural polyphenols and various metal ions. Diverse functional cargos, including anticancer drugs and proteins with different molecular weights and isoelectric points, are readily loaded within the NPs for various applications (e.g., biocatalysis, therapeutic delivery) by direct mixing, without surface modification, owing to the strong affinity of polyphenols to various guest molecules. This study provides insights into the assembly mechanism of metal-organic complexes into NPs and offers a simple strategy to engineer nanosized materials with desired properties for diverse biotechnological applications.

Keywords: Biomedicine; Coordination Assembly; Metal-Organic Networks; Nanoparticles; Polyphenols.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
a) Schematic of the direct assembly of MPN NPs and cargo‐loaded MPN NPs. b) Size, as determined by DLS, and ζ‐potential values of MPN NPs assembled using different concentrations of PB. Note that 0 and 0.1 mM PB did not result in MPN NP formation. Data are shown as the mean ± standard deviation (SD) (n=3). c) Time‐dependent DLS data, showing the growth of MPN NPs. d) Super‐resolution lattice SIM images of FITC‐labeled MPN NPs. Scale bars are 200 nm. e) TEM image of MPN NPs. Scale bar is 200 nm. f) AFM image of MPN NPs. Cross section given in Figure S8. Scale bar is 200 nm. g) FTIR spectra of QUE and MPN (FeII‐QUE) NPs.
Figure 2
Figure 2
a–c) Size, as determined by DLS (a), ζ‐potential values (b), and FeII‐to‐QUE ratio (c) of the MPN particles assembled at various pH values. Data are shown as the mean±SD (n=3). d) SEM image and e) EDX elemental mapping of MPN crystals obtained at pH 4. Scale bars are 1 μm. f) XRD patterns of MPN crystals and NPs. g) Percentages of Fe‐maltol, and tri‐state, bis‐state, and mono‐state Fe‐catechol coordination of the MPN particles as a function of assembly pH. h) FTIR spectra of MPN particles assembled at different pH values. i) Heatmap illustrating the stability of MPN crystals and NPs upon incubating in different media. EDTA, ethylenediaminetetraacetic acid; X‐100, Triton X‐100; DMF, dimethylformamide; THF, tetrahydrofuran. Y means stable and N means disassembled.
Figure 3
Figure 3
a) Chemical structures of the polyphenols used and their coordination modes with various metal ions (dashed box). Multimodal, catechol‐based, and maltol‐based polyphenol ligands are presented within the orange, green, and blue boxes, respectively. b) Library of MPN NPs with different size ranges fabricated using FeII and various polyphenols or using QUE and various metal ions in PB (pH 7). c) Size distribution and TEM image (inset) of BSA@MPN NPs. Scale bar is 200 nm. d) Stability of BSA@MPN NPs upon incubation in different media. e) ζ‐Potential values of BSA@MPN NPs, HRP@MPN NPs, and RNase A@MPN NPs at different pH values. Data are shown as the mean±SD (n=3). The NP sizes reported in (b–d) and PDI reported in (c) were determined by DLS.
Figure 4
Figure 4
a) Schematic of the cascade reaction by GOx/HRP@MPN NPs, involving glucose oxidation and conversion of amplex red to fluorescent resorufin. b) Relative catalytic activity of HRP@MPN NPs as a function of cycle number. c) CD spectra of native RNase A and RNase A released from NPs. d) CLSM image and related color scatter plot showing the intracellular localization of RNase A@MPN NPs in 3T3 cells after incubation for 4 h. Red, RNase A@MPN NPs; blue, nuclei; green, endosomes and lysosomes. Scale bar is 10 μm. e) CLSM images of anti‐CD44@MPN NPs and IgG@MPN NPs incubated with MDA‐MB‐231 cells for 3 h. Blue, nuclei; red, membrane. Scale bars are 3 μm. f) Flow cytometry analysis of the binding of anti‐CD44@MPN NPs and IgG@MPN NPs to MDA‐MB‐231 or BT‐474 cells after incubation for 1 h at 4 °C (left); percentage of MDA‐MB‐231 cells associated with anti‐CD44@MPN NPs or IgG@MPN NPs after incubation for 1 or 3 h at 37 °C (right). g) Viability of 3T3 cells after incubation with free DOX or DOX@MPN NPs at different drug dosages. Data are shown as the mean±SD (n=5).
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