Shihui Wen

• Doctor of Philosophy
• Research Associate at University of Technology Sydney

The COVID‐19 pandemic has underscored the critical need for rapid and accurate diagnostic tools. Current methods, including Polymerase Chain Reaction and rapid antigen tests (RAT), have limitations in speed, sensitivity, and the requirement for specialized equipment and trained personnel. Nanotechnology, particularly upconversion nanoparticles (UCN...

The COVID-19 pandemic has underscored the critical need for rapid and accurate diagnostic tools. Current methods, including PCR and rapid antigen tests (RAT), have limitations in speed, sensitivity, and the requirement for specialized equipment and trained personnel. Nanotechnology, particularly upconversion nanoparticles (UCNPs), offer a promising...

Precise force measurement is critical to probe biological events and physics processes, spanning from molecular motor’s motion to the Casimir effect, as well as the detection of gravitational waves. Yet, despite extensive technological developments, the three-dimensional nanoscale measurement of weak forces in aqueous solutions still faces major ch...

Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for causing life-threatening infections that result in high morbidity and mortality rates. The development of advanced imaging and therapeutic methods for in vivo diagnosis and treatment of MRSA infections remains challenging. Here, we develop a hybrid nanoplatform based on rare-eart...

Multiphoton upconversion super-resolution microscopy (MPUM) is a promising imaging modality, which can provide increased resolution and penetration depth by using nonlinear near-infrared emission light through the so-called transparent biological window. However, a high excitation power is needed to achieve emission saturation, which increases phot...

Preeclampsia is a heterogeneous and multiorgan cardiovascular disorder of pregnancy. Here, we report the development of a novel strip‐based lateral flow assay (LFA) using lanthanide‐doped upconversion nanoparticles conjugated to antibodies targeting two different biomarkers for detection of preeclampsia. We first measured circulating plasma FKBPL a...

Upconverting stimulated emission depletion microscopy (U‐STED) is emerging as an effective approach for super‐resolution imaging due to its significantly low depletion power and its ability to surpass the limitations of the square‐root law and achieve higher resolution. Though the compelling performance, a trade‐off between the spatial resolution a...

Preeclampsia is a heterogeneous and multiorgan cardiovascular disorder of pregnancy. Here, we report the development of a novel strip‐based lateral flow assay (LFA) using lanthanide‐doped upconversion nanoparticles conjugated to antibodies targeting two different biomarkers for detection of preeclampsia. We first measured circulating plasma FKBPL a...

Nanoscale weak force sensing in aqueous solution is of great interest to researchers from broad areas, including physics and biology. Here we developed a video tracking-based optical tweezers calibration method that enables the detection of the trap stiffness for low refractive index nanoparticles. We found that under resonance conditions, doping l...

Precise force measurement is critical to probing biological events and physics processes, spanning from molecular motor’s motion to the Casimir effect ¹ and the detection of gravitational wave ² . Yet, despite extensive technology developments, the 3D nanoscale measurement of weak forces in aqueous solutions poses a significant challenge. Technique...

Although small EVs (sEVs) have been used widely as biomarkers in disease diagnosis, their heterogeneity at single EV level has rarely been revealed. This is because high-resolution characterization of sEV presents a major challenge, as their sizes are below the optical diffraction limit. Here, we report that upconversion nanoparticles (UCNPs) can b...

The unique optical properties of lanthanide-doped nanomaterials have made them broadly attractive to a wide range of applications in chemical, physical, and biomedical fields. As an external and real-time regulation tool, the magnetic field is highly useful for modulating the luminescence of lanthanide ions by spectral splitting, wavelength shiftin...

Lanthanide-doped upconversion nanoparticles (UCNPs) have enabled a broad range of emerging nanophotonics and biophotonics applications. Here, we provide a quantitative guide to the optimum concentrations of Yb3+ sensitizer and Tm3+ emitter ions, highly dependent on the excitation power densities. To achieve this, we fabricate the inert-core@active-...

Cancer-derived small extracellular vesicles (sEVs) are potential circulating biomarkers in liquid biopsies. However, their small sizes, low abundance, and heterogeneity in molecular makeups pose major technical challenges for detecting and characterizing them quantitatively. Here, we demonstrate a single-sEV enumeration platform using lanthanide-do...

The central nervous system (CNS) is protected by the blood-brain barrier (BBB), which acts as a physical barrier to regulate and prevent the uptake of endogenous metabolites and xenobiotics. However, the BBB prevents most non-lipophilic drugs from reaching the CNS following systematic administration. Therefore, there is considerable interest in ide...

Upconversion nanoparticles (UCNPs) are typically doped with lanthanide ions, capable of converting near-infrared light into visible and ultraviolet emissions. Their unique optical properties have attracted considerable research interests and enabled various applications ranging from molecular detection, bioimaging, nanomedicine, to volumetric displ...

Sensitive and quantitative detection of molecular biomarkers is crucial for the early diagnosis of diseases like metabolic syndrome and cancer. Here we present a single-molecule sandwich immunoassay by imaging the number of single nanoparticles to diagnose aggressive prostate cancer. Our assay employed the photo-stable upconversion nanoparticles (U...

Optical tweezers are widely used in materials assembly¹, characterization², biomechanical force sensing3,4 and the in vivo manipulation of cells⁵ and organs⁶. The trapping force has primarily been generated through the refractive index mismatch between a trapped object and its surrounding medium. This poses a fundamental challenge for the optical t...

Sub-diffraction limited localization of fluorescent emitters is a key goal of microscopy imaging. Here, we report that single upconversion nanoparticles, containing multiple emission centres with random orientations, can generate a series of unique, bright and position-sensitive patterns in the spatial domain when placed on top of a mirror. Support...

The ability of upconversion nanoparticles (UCNPs) to convert low-energy near-infrared (NIR) light into high-energy visible-ultraviolet light has resulted in their development as novel contrast agents for biomedical imaging. However, UCNPs often succumb to poor colloidal stability in aqueous media, which can be conquered by decorating the nanopartic...

Precise design and fabrication of heterogeneous nanostructures will enable nanoscale devices to integrate multiple desirable functionalities. But due to the diffraction limit (~200 nm), the optical uniformity and diversity within the heterogeneous functional nanostructures are hardly controlled and characterized. Here, we report a set of heterogene...

Coordination chemistry has been widely studied in lanthanide complexes, where organic ligands are used to chelate individual lanthanide ions, and the complexes are broadly used in analytical, biological, and clinical applications. Significant progress has recently been made to exploit the hybrid structure of lanthanide doped inorganic nanoparticles...

One of the major challenges in using upconversion nanoparticles (UCNPs) is to improve their brightness. This is particularly true for in vivo studies, as the low power excitation is required to prevent the potential photo toxicity to live cells and tissues. Here, we report that the typical NaYF4:Yb0.2,Er0.02 nanoparticles can be highly doped, and t...

Precise design and fabrication of heterogeneous nanostructures will enable nanoscale devices to integrate multiple desirable functionalities. But due to the diffraction limit (~200 nm), the optical uniformity and diversity within the heterogeneous functional nanostructures are hardly controlled and characterized. Here we report a set of nanobarcode...

We developed a video-rate upconverting display system with much enhanced brightness. The integral emission intensity of the single Volumetric displays that create bright image points within a transparent bulk is one of the most attracting technologies in everyday life. Lanthanide ions doped upconversion nanoparticles (UCNPs) is an promising lumines...

Video-rate super-resolution imaging through biological tissue can visualize and track biomolecule interplays and transportations inside cellular organisms. Structured illumination microscopy allows for wide-field super resolution observation of biological samples but is limited by the strong extinction of light by biological tissues, which restrict...

Photothermal therapy (PTT) has been widely used for the treatment of various medical conditions due to their noninvasive and cost-effective advantages. However, the light absorption and scattering of the biosystem limits the deep tissue applications of conventional PTT probes. In this paper, we proposed the sub-10 nm NaNdF4 nanocrystals with both i...

Video-rate super-resolution imaging through biological tissue can visualize and track biomolecule interplays and transportations inside cellular organisms. Structured illumination microscopy allows for wide-field super resolution observation of biological samples but is limited by the strong absorption and scattering of light by biological tissues,...

In article number 1905572, Fan Wang and co‐workers develop near‐infrared Bessel‐beam emission saturation nanoscopy to simultaneously tackle the problems in light absorption and scattering for biological tissues, enabling the tracking of single nanoparticles inside a multicellular tumor spheroid in the depth over 55 µm with an imaging resolution of...

Cancer spheroids have structural, functional, and physiological similarities to the tumor, and have become a low‐cost in vitro model to study the physiological responses of single cells and therapeutic efficacy of drugs. However, the tiny spheroid, made of a cluster of high‐density cells, is highly scattering and absorptive, which prevents light mi...

To improve the efficiency of photon upconversion, a hybrid approach of combining organic dyes and inorganic nanoparticles is proving successful, especially in the form of dye-sensitized lanthanide-doped upconversion nanoparticles, nanoparticle-sensitized molecular triplet–triplet annihilation systems and metal–organic-framework nanoparticles. In th...

Aim: We demonstrated a novel theranostic system for simultaneous photothermal therapy and magnetic resonance imaging applicable to early diagnostics and treatment of cancer cells. Materials & methods: Oleic acid-Fe3O4 and triphenylamine-divinylanthracene-dicyano were loaded to the poly(L-lactic-co-glycolic acid) nanoparticles (NPs) on which anti-VE...

Bright and photo-stable luminescent nanoparticles held great potential for bioimaging, long-term molecular tracking. Rare-earth-doped upconversion nanoparticles (UCNPs) have been recently discovered with unique properties for Stimulated Emission Depletion (STED) super-resolution microscopy imaging. However, this system strictly requires optical ali...

Lanthanide-doped upconversion nanoparticles (UCNPs) are the most efficient multi-photon probe that can be used for deep tissue bio-imaging, fluorescence microscopy, and single molecule sensing applications. Passivating UCNPs with inert shell has been demonstrated to be an effective method to significantly enhance their brightness. However, this met...

Lanthanide-doped upconversion nanoparticles (UCNPs) are capable of converting near-infra-red excitation into visible and ultraviolet emission. Their unique optical properties have advanced a broad range of applications, such as fluorescent microscopy, deep-tissue bioimaging, nanomedicine, optogenetics, security labelling and volumetric display. How...

Multiphoton fluorescence microscopy (MPM), using near infrared excitation light, provides increased penetration depth, decreased detection background, and reduced phototoxicity. Using stimulated emission depletion (STED) approach, MPM can bypass the diffraction limitation, but it requires both spatial alignment and temporal synchronization of high...

We report here a facile method for one-step loading of gold (Au) and gadolinium oxide (Gd2O3) nanoparticles (NPs) within polyethyleneimine (PEI) pre-modified with polyethtylene glycol (PEG) for dual mode computed tomography (CT) and magnetic resonance (MR) imaging of tumors. PEGylated PEI was used as a template to complex Au(III) and Gd(III) salts,...

We report a facile approach of using DNA molecules as switches to selectively activate silica coating onto specific facets of upconversion nanoparticles. Being simple and reproducible, this method improves the...

Despite significant advances toward accurate tuning of the size and shape of colloidal nanoparticles, precise control of the surface chemistry thereof remains a grand challenge. It is desirable to conjugate functional bio-molecules onto the selected facets of the nanoparticles owing to the versatile capabilities rendered by the molecules. We report...

Nanoparticles have become new tools for cell biology imaging, sub-cellular sensing, super-resolution imaging, and drug delivery. Long-term 3D tracking of nanoparticles and their intracellular motions have advanced the understanding of endocytosis and exocytosis as well as of active transport processes. The sophisticated operation of correlative opt...

Thermal quenching, in which light emission experiences a loss with increasing temperature, broadly limits luminescent efficiency at higher temperature in optical materials, such as lighting phosphors1–3 and fluorescent probes4–6. Thermal quenching is commonly caused by the increased activity of phonons that leverages the non-radiative relaxation pa...

Upconversion nanoparticles (UCNPs) are new optical probes for biological applications. To realize specific biomolecular recognition for diagnosis and imaging, the key lies in developing a stable and easy-to-use bioconjugation method for antibody modification. Current methods are not yet satisfactory regarding conjugation time, stability, and bindin...

In this study, we report the synthesis, characterization and utilization of 99mTc-labelled polyethylenimine-entrapped gold nanoparticles (99mTc-Au-PENPs) for dual mode single-photon emission computed tomography/computed tomography (SPECT/CT) imaging applications. Polyethylenimine (PEI) was selected as a platform to conjugate with diethylene triamin...

Despite intense efforts on surface functionalization to generate hydrophilic upconversion nanoparticles (UCNPs), long-term colloidal stability in physiological buffers remains a major concern. Here we quantitatively investigate the competitive adsorption of phosphate, carboxylic acid and sulphonic acid onto the surface of UCNPs and study their bind...

Sensitivity is the key in optical detection of low-abundant analytes, such as circulating RNA or DNA. The enzyme Exonuclease III (Exo III) is a useful tool in this regard; its ability to recycle target DNA molecules results in markedly improved detection sensitivity. Lower limits of detection may be further achieved if the detection background of a...

The key to produce inorganic heterogeneous nanostructures, and to integrate multiple functionalities, is to enhance or at least retain the functionalities of different components of materials. However, this ideal scenario is often deteriorated at the interface of the heterogeneous nanostructures due to the lattice mismatches, resulting in downgrade...

Multifunctional 99mTc-labeled dendrimer-entrapped gold nanoparticles (99mTc-Au DENPs) were designed and synthesized. Our results show that the type of surface groups (acetyl or hydroxyl) significantly impact the biodistribution profile of the 99mTc-Au DENPs, thereby allowing for preferential SPECT/CT imaging of different organs.

We report the synthesis and characterization of lactobionic acid-modified multifunctional polyethyleneimine-entrapped gold nanoparticles for targeted dual mode computed tomography/magnetic resonance imaging. The nanodevice displays good X-ray attenuation properties, good r1 relaxivity, and hepatocellular carcinoma targeting specificity, and can be...

Lanthanide-doped glasses and crystals are attractive for laser applications because the metastable energy levels of the trivalent lanthanide ions facilitate the establishment of population inversion and amplified stimulated emission at relatively low pump power. At the nanometre scale, lanthanide-doped upconversion nanoparticles (UCNPs) can now be...

Optical biomedical imaging using luminescent nanoparticles as contrast agents prefers small size, as they can be used at high dosages and efficiently cleared from body. Reducing nanoparticle size is critical for the stability and specificity for the fluorescence nanoparticles probes for in vitro diagnostics and sub-cellular imaging. The development...

The advancement of biocompatible nanoplatforms with dual functionalities of diagnosis and therapeutics has been strongly demanded in biomedicine in recent years. In this work, we report the synthesis and characterization of polydopamine (pD)-coated gold nanostars (Au NSs) for computed tomography (CT) imaging and enhanced photothermal therapy (PTT)...

Gene therapies represent a promising therapeutic route for liver cancers, but major challenges remain in the design of safe and efficient gene-targeting delivery systems. For example, cationic polymers show good transfection efficiency as gene carriers, but are hindered by cytotoxicity and non-specific targeting. Here we report a versatile method o...

Development of new long-circulating contrast agents for computed tomography (CT) imaging of different biological systems still remains a great challenge. Here, we report the design and synthesis of branched polyethyleneimine (PEI)-stabilized gold nanoparticles (Au PSNPs) modified with polyethylene glycol (PEG) for blood pool, lymph node, and tumor...

The ultimate frontier in nanomaterials engineering is to realize their composition control with atomic scale precision to enable fabrication of nanoparticles with desirable size, shape and surface properties. Such control becomes even more useful when growing hybrid nanocrystals designed to integrate multiple functionalities. Here we report achievi...

Supplementary Figures 1-35, Supplementary Tables 1-3, Supplementary Notes 1-18, Supplementary Methods and Supplementary References

The facile hydrothermal synthesis of polyethyleneimine (PEI)-coated iron oxide (Fe3O4) nanoparticles (NPs) doped with Gd(OH)3 (Fe3O4-Gd(OH)3-PEI NPs) for dual mode T1- and T2-weighted magnetic resonance (MR) imaging applications is reported. In this approach, Fe3O4-Gd(OH)3-PEI NPs are synthesized via a hydrothermal method in the presence of branche...

A unique dendrimer-assisted approach is reported to create Fe3 O4 /Au nanocomposite particles (NCPs) for targeted dual mode computed tomography/magnetic resonance (CT/MR) imaging of tumors. In this approach, preformed Fe3 O4 nanoparticles (NPs) are assembled with multilayers of poly(γ-glutamic acid) (PGA)/poly(l-lysine)/PGA/folic acid (FA)-modified...

Gene therapy has been concerned to be one of the most promising strategies to treat many diseases such as genetic disorders and cancer. However, design of safe and highly efficient gene delivery vectors still remains a great challenge. In this work, we report the use of partially acetylated dendrimer-entrapped gold nanoparticles (Au DENPs) for gene...

We report the use of multifunctional dendrimer-entrapped gold nanoparticles (Au DENPs) loaded with gadolinium (Gd) chelator/Gd(III) complexes and surface modified with thiolated cyclo(Arg-Gly-Asp-Phe-Lys(mpa)) (RGD) peptide for targeted dual mode computed tomography (CT)/magnetic resonance (MR) imaging of small tumors. In this study, amine-terminat...

This review reports the recent advances in dendrimer‐entrapped metal colloids as contrast agents for biomedical imaging applications. The versatile dendrimer scaffolds with 3‐dimensional spherical shape, highly branched internal cavity, tunable surface conjugation chemistry, and excellent biocompatibility and nonimmunogenicity afford their uses as...

Long-circulating multifunctional Gd(III)-loaded multiwalled carbon nanotubes (MWCNTs) modified with polyethylene glycol are designed and synthesized. The formed MWCNTs are water-dispersible, stable, and have good cytocompatibility and antifouling property. With the low r 2 /r 1 relaxivity ratio and relatively long blood circulation time, the multif...

Long-circulating multifunctional Gd(III)-loaded multiwalled carbon nanotubes (MWCNTs) modified with polyethylene glycol are designed and synthesized by W. Zhu, X. Shi, and colleagues on page 1568. The formed MWCNTs are water-dispersible, stable, and have good cytocompatibility and antifouling property. With the low r2 /r1 relaxivity ratio and relat...

The synthesis and characterization of gold nanoparticles (AuNPs) entrapped within polyethylene glycol (PEG)-modified polyethyleneimine (PEI) for blood pool and tumor computed tomography (CT) imaging are reported. In this approach, partially PEGylated PEI was used as a template for AuNP synthesis, followed by acetylating the PEI remaining surface am...

We report here an effective approach to modifying laponite (LAP) nanodisks with folic acid (FA) for targeted anticancer drug delivery applications. In this approach, LAP nanodisks were first modified with 3-aminopropyldimethylethoxysilane (APMES) to render them with abundant surface amines, followed by conjugation with FA via 1-ethyl-3-(3-dimethyla...

We report the development of a lactobionic acid (LA)-modified multifunctional dendrimer-based carrier system for targeted therapy of liver cancer cells overexpressing asialoglycoprotein receptors. In this study, generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers were sequentially modified with fluorescein isothiocyanate (FI) and LA (or polyethyl...

We report here the fabrication, characterization and use of poly(lactic-co-glycolic acid) (PLGA) hollow microcapsules (HMs) loaded with the anticancer drug doxorubicin (DOX) for targeted drug delivery to cancer cells. In this study, PLGA HMs loaded with DOX (PLGA–DOX HMs) were prepared by a double emulsion method, followed by electrostatic assembly...

Development of various nanoscale drug carriers for enhanced antitumor therapy still remains a great challenge. In this study, laponite (LAP) nanodisks encapsulated with anticancer drug doxorubicin (DOX) at an exceptionally high loading efficiency (98.3 ± 0.77%) were used for tumor therapy applications. The long-term in vivo antitumor efficacy and t...

Development of novel drug carriers for targeted cancer therapy with high efficiency and specificity is of paramount importance and has been one of the major topics in current nanomedicine. Here we report a general approach to using multifunctional multiwalled carbon nanotubes (MWCNTs) as a platform to encapsulate an anticancer drug doxorubicin (DOX...

We report here the fabrication, characterization and use of PLGA hollow microbubbles (HMs) loaded with iron oxide (Fe3O4) nanoparticles (NPs) and anticancer drug doxorubicin (DOX) for dual-mode ultrasound (US)/magnetic resonance (MR) imaging and drug delivery applications. In this study, a double emulsion technique was employed to prepare PLGA HMs,...

Development of novel nanomaterials-based contrast agents for targeted computed tomography (CT) imaging of tumors still remains a great challenge. Here we describe a novel approach to fabricating lactobionic acid (LA)-modified dendrimer-entrapped gold nanoparticles (LA-Au DENPs) for in vitro and in vivo targeted CT imaging of human hepatocellular ca...

Removal of hazardous metal ions from industrial wastewater is of paramount importance. Taking advantage of the metal–ligand binding specificity and electrospun nanofibers with a high surface area to volume ratio and a porous structure, we developed thymine (T)-grafted poly(vinyl alcohol) (PVA)–polyethyleneimine (PEI) nanofibers for selective remova...

We report a new use of dendrimer-entrapped gold nanoparticles (Au DENPs) modified with folic acid (FA) as a non-viral vector for targeted gene delivery applications. In this study, amine-terminated generation 5 poly(amidoamine) dendrimers modified with FA via covalent conjugation were used as templates to synthesize gold nanoparticles with an Au sa...

We report here the use of dendrimer-stabilized silver nanoparticles (Ag DSNPs) for the highly sensitive and selective colorimetric detection of mercury ions (Hg2+) in aqueous solution. In this study, amine-terminated generation 5 poly( amidoamine) dendrimers were employed as stabilizers to complex Ag+ ions for the subsequent reductive formation of...