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WIREs Nanomed Nanobiotechnol
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Going even smaller: Engineering sub‐5 nm nanoparticles for improved delivery, biocompatibility, and functionality

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Abstract The rapid development and advances in nanomaterials and nanotechnology in the past two decades have made profound impact in our approaches to individualized disease diagnosis and treatment. Nanomaterials, mostly in the range of 10–200 nm, developed for biomedical applications provide a wide range of platforms for building and engineering functionalized structures, devices, or systems to fulfill the specific diagnostic and therapeutic needs. Driven by achieving the ultimate goal of clinical translation, sub‐5 nm nano‐constructs, in particular inorganic nanoparticles such as gold, silver, silica, and iron oxide nanoparticles, have been developed in recent years to improve the biocompatibility, delivery and pharmacokinetics of imaging probes and drug delivery systems, as well as in vivo theranostic applications. The emerging studies have provided new findings that demonstrated the unique size‐dependent physical properties, physiological behaviors and biological functions of the nanomaterials in the range of the sub‐5 nm scale, including renal clearance, novel imaging contrast, and tissue distribution. This advanced review attempts to introduce the new strategies of rational design for engineering nanoparticles with the core sizes under 5 nm in consideration of the clinical and translational requirements. We will provide readers the update on recent discoveries of chemical, physical, and biological properties of some biocompatible sub‐5 nm nanomaterials as well as their demonstrated imaging and theranostic applications, followed by sharing our perspectives on the future development of this class of nanomaterials. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Implantable Materials and Surgical Technologies > Nanomaterials and Implants
3D and cross‐sectional re‐construction of multiphoton microscopic images taken from an 8 mm3 tumor tissue block collected from 4T1 tumor‐bearing mice co‐injected with active targeting FITC‐Tf‐uIONPs (green) and nontargeting TRITC‐uIONPs (red) at different time points (with the selected cross‐sections) (a). Tumor collagen was visualized using second harmonic generation (SHG), and presented as bright signals in a grayscale setting. The scale bar for all images is 50 μm. Confocal microscopic images of tissue sections containing FITC‐Tf‐uIONPs (green) and nontargeting TRITC‐uIONPs (red) and DAPI was used to stain the nuclei, and H&E stained for tissue morphology (b). Time‐dependent changes of actively targeted uIONPs based on multiphoton imaging quantification showed high accumulation of ligand mediated actively targeted uIONPs comparing to passively targeted controls (c). Adopted from Xu et al. (2020) with permission from the authors
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The possible mechanism of improving EPR driven delivery of nanoparticles at sub‐5 nm scale (a). Multiphoton imaging revealed size‐dependent tumor tissue penetration and intratumoral distribution in favor to sub‐5 nm uIONPs (green) comparing to larger 20‐nm core IONPs (red) co‐injected to the mice bearing 4T1 breast tumors (b). MRI with compartment specific T1–T2 contrast switching from uIONPs and iron quantification from the tissue section confirmed size‐dependent increase of tumor uptake (c). Adopted with permission from reference (Wang et al., 2017), Copyright © 2018, American Chemical Society)
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Sub‐5 nm nanoparticles are renally clearable with clearance efficiency controllable based on the size and surface properties. (a) The renal clearance efficiencies of Au10–11, Au15, Au18 and Au25, 1.7 nm (Au201), 2.5 nm (Au640), and 6 nm (Au8856) GS‐AuNPs 24 hr postinjection over the number of gold atoms. Below Au25, the renal clearance efficiency exponentially decreased with the decrease of the number of gold atoms in the NPs (adopted from Du et al. (2018) with permission). (b) Illustration of the components of glomerulus. The glomerular filtration membrane is composed of multiple layers: endothelial glycocalyx, endothelial cell, glomerular basement membrane (GBM), and podocyte (adapted from with permission the reference (Du et al., 2018). (c) T1‐weighted (top row) and T2‐weighted MRI shows the time‐dependent contrast changes in the bladder of a mouse injected with 3‐nm core uIONP, as renally excreted uIONP slowly filling the bladder (adopted from Huang et al. (2014) with permission). (d) 3D volume‐rendered CT images of a mouse injected with GSH coated Ag2S nanoparticles with an average core diameter of 3.1 nm. Green circles indicate the bladder which was filled by CT‐sensitive Ag2S nanoparticles 5 min after the injection. Hearts and kidneys are labeled H and K, respectively (adopted from Hsu et al. (2019) with permission from the authors)
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Clearance studies of i.v. administered 3 nm SIO nanoparticles at 2.5 mg Fe/kg in BALB/c mice. (a) Pseudo colored T2‐wiehgted MR images following up the clearance of nanoparticles in liver (L) and spleen (S). The corresponding signal change for (b) liver and (c) spleen in T2‐maps (n = 3). Adapted from Huang et al. (2014) with permission
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Examples of surface coating approaches to render sub‐5 nm nanoparticle water soluble and stable. (a) Anchoring zwitterionic glutathione molecules to the nanoparticle surface via chemical bonds (Gong et al., 2017; Hsu et al., 2019; Peng et al., 2017; Tang et al., 2016a). (b) Forming a thin layer of oligosaccharide on the nanoparticle surface via “in situ polymerization” of glucose. (c) Photographs of oligosaccharide solutions under normal light (upper) and UV light (bottom) at the different stages during the polymerization reaction (adopted from Huang et al. (2014) with permission)
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TEM images of 2.2 and 3.7 nm iron oxide nanoparticles (a). The size of ESIONs can be controlled by changing aging temperature and solvents. XRD patterns show resulted ESIONs with maghemite (γ‐Fe2O3; JCPDS no. 39‐1346) crystal structure (b) and size‐dependent magnetization. Images are adopted with permission from the reference (Kim et al., 2011), Copyright © 2011, American Chemical Society. (c) The size of AgS nanoparticles can be manipulated by changing the reaction time and temperature (c) demonstrated by Hsu et al. (2019). Images are adopted from Hsu et al. (2019) with permission
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Tuning MRI contrast with sub‐5 nm magnetic iron oxide nanoparticles. Magnetization of the nanoparticles is size‐dependent with reduced magnetic moment and susceptibility in sub‐5 nm scale (a, adopted from Kim et al. (2011) with permission, Copyright © 2011, American Chemical Society). Reducing the nanoparticle size leads to high r1/r2 ratio (b) and enhanced vasculature and kidney by 3‐nm SIO‐3 in T1‐weighted MRI at the field strength of 3 T (c), adopted from Huang et al. (2014) with permission. By modulating the surface coating, T1 and T2 dual contrast can be optimized as shown in MRI of subcutaneous tumors (d, adopted from Zhou et al. (2017) with permission, Copyright © 2017, American Chemical Society)
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TEM images of PEG‐b‐AGE coated IONPs with core diameters of 3.5 (a), 10 (b), and 20 (c) nm and the hydrodynamic diameters of these IONPs in water (d) reveal their stability in aqueous solution. The varied loading efficiencies of DOX onto PEG‐b‐AGE coated IONPs with 3.5, 10, and 20 nm core diameters decreased at pH 5.0 (e), suggesting IONPs with smaller size have higher payload loading efficiency while having little effect on the payload release. The surface densities of RGD ligands conjugated to each IONP significantly decreased as the core diameters of IONPs increased from 3.5 to 20 nm (f), indicating the higher ligand density on smaller IONPs than that on the larger ones
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Implantable Materials and Surgical Technologies > Nanomaterials and Implants
Diagnostic Tools > In Vivo Nanodiagnostics and Imaging

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