Publications by authors named "Yannan Yang"

51 Publications

Ferroptosis-Strengthened Metabolic and Inflammatory Regulation of Tumor-Associated Macrophages Provokes Potent Tumoricidal Activities.

Nano Lett 2021 08 22;21(15):6471-6479. Epub 2021 Jul 22.

School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, People's Republic of China.

Modulation of tumor-associated macrophages (TAMs) holds promise for cancer treatment, mainly relying on M1 signaling activation and pro-inflammatory promotion. Nevertheless, the antitumor activity is often limited by the anti-inflammatory factors in the tumor microenvironment. Moreover, the metabolic function of TAMs is also critical to tumor progression. However, there are a few strategies that can simultaneously regulate both inflammatory and metabolic functions to achieve safe and potent antitumor activation of TAMs. Herein, we demonstrate that an iron-based metal organic framework nanoparticle and a ferroptosis-inducing agent synergistically induce mitochondrial alternation in TAMs, resulting in a radical metabolic switch from mitochondrial oxidative phosphorylation to glycolysis, which is resistant to anti-inflammatory stimuli challenge. The ferroptosis stress strengthened by the nanoformulation also drives multiple pro-inflammatory signaling pathways, enabling macrophage activation with potent tumoricidal activities. The ferroptosis-strengthened macrophage regulation strategy present in this study paves the way for TAM-centered antitumoral treatment to overcome the limitations of conventional methods.
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http://dx.doi.org/10.1021/acs.nanolett.1c01401DOI Listing
August 2021

Author Correction: METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N-methyladenosine-dependent YTHDF binding.

Nat Commun 2021 Jul 20;12(1):4529. Epub 2021 Jul 20.

Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.

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http://dx.doi.org/10.1038/s41467-021-24860-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292537PMC
July 2021

METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N-methyladenosine-dependent YTHDF binding.

Nat Commun 2021 06 21;12(1):3803. Epub 2021 Jun 21.

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

The adenomatous polyposis coli (APC) is a frequently mutated tumour suppressor gene in cancers. However, whether APC is regulated at the epitranscriptomic level remains elusive. In this study, we analysed TCGA data and separated 200 paired oesophageal squamous cell carcinoma (ESCC) specimens and their adjacent normal tissues and demonstrated that methyltransferase-like 3 (METTL3) is highly expressed in tumour tissues. mA-RNA immunoprecipitation sequencing revealed that METTL3 upregulates the mA modification of APC, which recruits YTHDF for APC mRNA degradation. Reduced APC expression increases the expression of β-catenin and β-catenin-mediated cyclin D1, c-Myc, and PKM2 expression, thereby leading to enhanced aerobic glycolysis, ESCC cell proliferation, and tumour formation in mice. In addition, downregulated APC expression correlates with upregulated METTL3 expression in human ESCC specimens and poor prognosis in ESCC patients. Our findings reveal a mechanism by which the Wnt/β-catenin pathway is upregulated in ESCC via METTL3/YTHDF-coupled epitranscriptomal downregulation of APC.
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http://dx.doi.org/10.1038/s41467-021-23501-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217513PMC
June 2021

Post translational modification-assisted cancer immunotherapy for effective breast cancer treatment.

Chem Sci 2020 Sep 10;11(38):10421-10430. Epub 2020 Sep 10.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland QLD 4072 Australia

Post translational modifications (PTM) such as phosphorylation are often correlated with tumorigenesis and malignancy in breast cancer. Herein, we report a PTM-assisted strategy as a simplified version of a personalized cancer vaccine for enhanced cancer immunotherapy. Titanium modified dendritic mesoporous silica nanoparticles (TiDMSN) are applied to assist the specific enrichment of phosphorylated tumor antigens released upon immunogenic cell death. This strategy significantly improved the tumor inhibition efficacy in a bilateral breast cancer model and the expansion of both CD8 and CD4 T cells in the distant tumor site. The nanotechnology based PTM-assisted strategy provides a simple and generalizable methodology for effective personalized cancer immunotherapy.
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http://dx.doi.org/10.1039/d0sc02803gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162284PMC
September 2020

Synthesis of dendritic mesoporous organosilica nanoparticles under a mild acidic condition with homogeneous wall structure and near-neutral surface.

Chem Commun (Camb) 2021 May;57(36):4416-4419

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia. and School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, P. R. China.

Dendritic mesoporous organosilica nanoparticles were synthesized under a mild acidic condition (pH 6.2), featuring a molecularly homogeneous wall structure and an unusual near-neutral charged surface, consequently enabling reduced protein fouling property.
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http://dx.doi.org/10.1039/d0cc08017aDOI Listing
May 2021

Designer Anticancer Nanoprodrugs with Self-Toxification Activity Realized by Acid-triggered Biodegradation and In Situ Fragment Complexation.

Angew Chem Int Ed Engl 2021 05 6;60(20):11504-11513. Epub 2021 Apr 6.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St. Lucia, Brisbane, QLD, 4072, Australia.

Prodrugs that allow in situ chemical conversion of less toxic precursors into active drugs in response to certain stimuli are promising anticancer candidates. Herein, we present a novel design of nanoprodrugs with a "degradation-mediated self-toxification" strategy, which realizes intracellular synthesis of anticancer agents using the nanoparticles' own degradation fragments as the precursors. To fulfill this concept, a metal complexing dicyclohexylphosphine (DCP) organosilane is carefully screened out from various ligands to conjugate onto Pd(OH) nanodots confined hollow silica nanospheres (PD-HSN). This constructed nanoprodrug shows acid-triggered degradation in lysosomes and neutralizes protons to induce lysosomes rupturing, generating predesigned less toxic fragments (Pd and DCP-silicates) that complex into DCP/Pd complex in situ for inducing DNA damage, leading to enhanced anticancer activity against various cancer cell lines as well as in a xenograft tumour model.
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http://dx.doi.org/10.1002/anie.202102704DOI Listing
May 2021

Construction and Comprehensive Analyses of a METTL5-Associated Prognostic Signature With Immune Implication in Lung Adenocarcinomas.

Front Genet 2020 19;11:617174. Epub 2021 Feb 19.

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

For lung adenocarcinoma (LUAD), patients of different stages have strong heterogeneity, and their overall prognosis varies greatly. Thus, exploration of novel biomarkers to better clarify the characteristics of LUAD is urgent. Multi-omics information of LUAD patients were collected form TCGA. Three independent LUAD cohorts were obtained from gene expression omnibus (GEO). A multi-omics correlation analysis of was performed in TCGA dataset. To build a -associated prognostic score (MAPS). Spathial and random forest methods were first applied for feature selection. Then, LASSO was implemented to develop the model in TCGA cohort. The prognostic value of MAPS was validated in three independent GEO datasets. Finally, functional annotation was conducted using gene set enrichment analysis (GSEA) and the abundances of infiltrated immune cells were estimated by ImmuCellAI algorithm. A total of 901 LUAD patients were included. The expression of in LUAD was significantly higher than that in normal lung tissue. And high expression of indicated poor prognosis in all different stages ( < 0.001, HR = 1.81). Five genes (, and ) were used to construct MAPS and MAPS was significantly correlated with poor prognosis ( < 0.001, HR = 2.15). Furthermore, multivariate Cox regression analysis suggested MAPS as an independent prognostic factor. Functional enrichment revealed significant association between MAPS and several immune components and pathways. This study provides insights into the potential significance of in LUAD and MAPS can serve as a promising biomarker for LUAD.
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http://dx.doi.org/10.3389/fgene.2020.617174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933593PMC
February 2021

MnO Nanoflowers Induce Immunogenic Cell Death under Nutrient Deprivation: Enabling an Orchestrated Cancer Starvation-Immunotherapy.

Adv Sci (Weinh) 2021 Feb 31;8(4):2002667. Epub 2020 Dec 31.

Australian Institute for Bioengineering and Nanotechnology The University of Queensland St. Lucia Brisbane QLD 4072 Australia.

MnO nanoparticles have been widely employed in cancer immunotherapy, playing a subsidiary role in assisting immunostimulatory drugs by improving their pharmacokinetics and/or creating a favorable microenvironment. Here, the stereotype of the subsidiary role of MnO nanoparticles in cancer immunotherapy is challenged. This study unravels an intrinsic immunomodulatory property of MnO nanoparticles as a unique nutrient-responsive immunogenic cell death (ICD) inducer, capable of directly modulating immunosurveillance toward tumor cells. MnO nanoflowers (MNFs) constructed via a one pot self-assembly approach selectively induce ICD to nutrient-deprived but not nutrient-replete cancer cells, which is confirmed by the upregulated damage associated molecular patterns in vitro and a prophylactic vaccination in vivo. The underlying mechanism of the MNFs-mediated selective ICD induction is likely associated with the concurrently upregulated oxidative stress and autophagy. Built on their unique immunomodulatory properties, an innovative nanomaterials orchestrated cancer starvation-immunotherapy is successfully developed, which is realized by the in situ vaccination with MNFs and vascular disrupting agents that cut off intratumoral nutrient supply, eliciting potent efficacy for suppressing local and distant tumors. These findings open up a new avenue toward biomedical applications of MnO materials, enabling an innovative therapeutics paradigm with great clinical significance.
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http://dx.doi.org/10.1002/advs.202002667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887587PMC
February 2021

Surfactant-free synthesis of monodispersed organosilica particles with pure sulfide-bridged silsesquioxane framework chemistry via extension of Stöber method.

J Colloid Interface Sci 2021 Jun 2;591:129-138. Epub 2021 Feb 2.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland 4072, Australia. Electronic address:

Sulfide bond incorporated organosilica particles have been broadly applied to versatile biomedical applications, wherein the uniformity of particles and the sulfur content significantly dictate the ultimate performance. Unfortunately, due to the difficulty in controlling the chemical behavior of organosilica precursors in a sol-gel process, challenges still exist in developing a facile and green synthetic approach to fabricate organosilica particles with good dispersity and high sulfur content. In the present work, by extending the classic Stöber method, a surfactant-free synthesis of monodispersed organosilica particles with pure sulfide-bridged silsesquioxane framework chemistry is reported for the first time. By simply tailoring the ethanol-to-water ratio and amount of catalyst, the size of disulfide-bridged organosilica particles can be tuned from ~0.50 to ~1.20 µm. Moreover, this approach can be employed to prepare tetra-sulfide bridged silica nanoparticles with an extremely high sulfur content of 30.7 wt% and negligible cytotoxicity. Notably, taking advantage of this extended Stöber method, both hydrophilic (methylene blue) and hydrophobic (curcumin) molecules can be in-situ encapsulated into tetra-sulfide bridged silica nanoparticles, whose glutathione-triggered biodegradability is also demonstrated. Collectively, the innovative synthetic approach and organosilica particles developed in this work are expected to open up new opportunities in hybrid materials fabrication and bio-applications.
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http://dx.doi.org/10.1016/j.jcis.2021.01.071DOI Listing
June 2021

Successful treatment of a patient with multi-site infection of cerebrospinal fluid and testis due to Klebsiella pneumoniae.

Acta Biochim Biophys Sin (Shanghai) 2021 Mar;53(4):511-513

Department of Intensive Care Unit, China Coast Guard Hospital of the People's Armed Police Force, Jiaxing 314001, China.

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http://dx.doi.org/10.1093/abbs/gmab004DOI Listing
March 2021

Dendritic Mesoporous Silica Nanoparticle Adjuvants Modified with Binuclear Aluminum Complex: Coordination Chemistry Dictates Adjuvanticity.

Angew Chem Int Ed Engl 2020 10;59(44):19610-19617

Australian Institute for Bioengineering and Nanotechnology, UQ-JLU Joint Research Centre for Future Materials, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia.

Aluminum-containing adjuvants used in vaccine formulations suffer from low cellular immunity, severe aggregation, and accumulation in the brain. Conventional aluminosilicates widely used in the chemical industry focus mainly on acidic sites for catalytic applications, but they are rarely used as adjuvants. Reported here is an innovative "ligand-assisted steric hindrance" strategy to create a high density of six-coordinate Al-OH groups with basicity on dendritic mesoporous silica nanoparticles as new nanoadjuvants. Compared to four-coordinate Al-modified counterparts, Al-OH-rich aluminosilicate nanoadjuvants enhance cellular delivery of antigens and provoke stronger cellular immunity. Moreover, the aluminum accumulation in the brain is more reduced than that with a commercial adjuvant. These results show that coordination chemistry can be used to control the adjuvanticity, providing new understanding in the development of next-generation vaccine adjuvants.
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http://dx.doi.org/10.1002/anie.202006861DOI Listing
October 2020

Eliciting Immunogenic Cell Death via a Unitized Nanoinducer.

Nano Lett 2020 09 14;20(9):6246-6254. Epub 2020 Aug 14.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia.

Utilizing chemotherapeutics to induce immunogenic cell death (ICD) is a promising strategy to sensitize tumor cells and induce anticancer immunity. However, the application of traditional ICD inducers, such as chemodrugs, is largely hindered by their low tumor selectivity and severe side effects. Here, a new unitized ICD nanoinducer with high potency and cancer cell specificity is reported to achieve effective cancer immunotherapy. This nanoinducer is composed of disulfide-bond-incorporated organosilica nanoparticles, curcumin (CUR), and iron oxide nanoparticles, which can deplete intracellular glutathione, produce hydroxyl radicals, and induce cancer-cell-specific Ca depletion as well as thioredoxin reductase inhibition. While the components are unable to induce ICD individually, their complementary pharmaceutical activities significantly elevate intracellular oxidative stress and endoplasmic reticulum stress in parallel. Consequently, ICD and systemic antitumor immunity can be elicited. Compared to the conventional ICD inducer doxorubicin, the unitized nanoinducer exhibits significantly improved ICD-inducing activity and cancer cell selectivity.
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http://dx.doi.org/10.1021/acs.nanolett.0c00713DOI Listing
September 2020

[email protected] Mesoporous Silica Nanoparticles for Lactate Depletion and Tumor Microenvironment Regulation.

Angew Chem Int Ed Engl 2020 12 7;59(49):22054-22062. Epub 2020 Oct 7.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia.

The direct depletion of lactate accumulated in the tumor microenvironment holds promise for cancer therapy but remains challenging. Herein, we report a one-pot synthesis of [email protected] dendritic mesoporous silica nanoparticles (ODMSNs) to address this problem. ODMSNs self-assembled through a time-resolved lamellar growth mechanism feature an openworked core and a dendritic shell, both constructed by silica nanosheets of ≈3 nm. With a large pore size, high surface area and pore volume, ODMSNs exhibited a high loading capacity (>0.7 g g ) of lactate oxidase (LOX) and enabled intratumoral lactate depletion by >99.9 %, leading to anti-angiogenesis, down-regulation of vascular endothelial growth factor, and increased tumor hypoxia. The latter event facilitates the activation of a co-delivered prodrug for enhancing anti-tumor and anti-metastasis efficacy. This study provides an innovative nano-delivery system and demonstrates the first example of direct lactate-depletion-enabled chemotherapy.
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http://dx.doi.org/10.1002/anie.202001469DOI Listing
December 2020

Silica-Based Nanoparticles for Biomedical Applications: From Nanocarriers to Biomodulators.

Acc Chem Res 2020 08 15;53(8):1545-1556. Epub 2020 Jul 15.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland 4072, Australia.

Silica-based nanoparticles (SNPs) are a classic type of material employed in biomedical applications because of their excellent biocompatibility and tailorable physiochemical properties. Typically, SNPs are designed as nanocarriers for therapeutics delivery, which can address a number of intrinsic drawbacks of therapeutics, including limited bioavailability, short circulation lifetime, and unfavorable biodistribution. To improve the delivery efficiency and spatiotemporal precision, tremendous efforts have been devoted to engineering the physiochemical properties of SNPs, including particle size, morphology, and mesostructure, as well as conjugating targeting ligands and/or "gatekeepers" to endow improved cell selectivity and on demand release profiles. Despite significant progress, the biologically inert nature of the bare silica framework has largely restricted the functionalities of SNPs, rendering conventional SNPs mainly as nanocarriers for targeted delivery and controlled release. To meet the requirements of next generation nanomedicines with improved efficacy and precision, new insights on the relationship between the physiochemical properties of SNPs and their biological behavior are highly valuable. Meanwhile, a conceptual shift from a simple spatiotemporal control mechanism to a more sophisticated biochemistry and signaling pathway modulation would be of great importance.In this Account, an overview of our recent contribution to the field is presented, wherein SNPs with rationally designed nanostructures and nanochemistry are applied as nanocarriers (defined as "nanomaterials being used as a transport module for another substance" according to Wikipedia) and/or biomodulators (defined as "any material that modifies a biological response" according to Wiktionary). This Account encompasses two main sections. In the first section, we focus on the conventional nanocarriers concept with new insights on the design principles of the nanostructures. We present examples to demonstrate the engineering of pore geometry, surface topology, and asymmetry of nanoparticles to achieve enhanced drug, gene, and protein delivery efficiency. The contribution of surface roughness of SNPs on improving the cellular uptake efficiency, adhesion property, and DNA transfection capacity is particularly highlighted. In the second section, we discuss novel SNPs designed as biomodulators to regulate intracellular microenvironment and cell signaling, such as the oxidative stress and glutathione levels for improving the anticancer efficacy of therapeutics and mRNA transfection in specific cell lines. The interplay between the nanoparticles, biological system, and drugs is discussed. We further discuss how to engineer the composition of SNPs to modulate metal hemostasis to realize inherent anticancer activity. Two typical examples, including modulating copper signaling for tumor vasculature targeted therapy and controlling iron signaling for macrophage polarization based immunotherapy, are presented to highlight the unique advantages of SNPs as nanosized therapeutics in comparison to molecular drugs. Moreover, utilizing these two examples, we showcase the possibility of designing SNPs with intrinsic pharmaceutical activity to indirectly control tumor growth without inducing significant cytotoxicity, thus alleviating the biosafety concerns of nanomedicines. At the end of this Account, we discuss our personal perspectives on the promises, opportunities, and issues in engineered SNPs as nanocarriers as well as their transition toward biomodulators. With a major focus on the latter scenario, the current status and possible future directions are outlined.
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http://dx.doi.org/10.1021/acs.accounts.0c00280DOI Listing
August 2020

Lyophilization enabled disentanglement of polyethylenimine on rambutan-like silica nanoparticles for enhanced plasmid DNA delivery.

J Mater Chem B 2020 06 11;8(21):4593-4600. Epub 2020 May 11.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia.

Polyethylenimine (PEI) functionalization onto nanoparticles is a widely used strategy for constructing particulate vectors for gene delivery. However, how to control the conformation of PEI chains and the resultant impact on gene transfection efficiency remains largely unexplored. Herein, we report that drying methods dramatically affect the conformation of PEI chains modified on the surface of silica nanoparticles and consequently the plasmid DNA transfection performance. Specifically, lyophilization renders less entangled PEI compared to commonly used vacuum drying as evidenced by an elevated glass transition temperature. The lyophilization induced disentangled conformation is likely associated with the solid-to-gas phase transition drying mechanism, which removes the bound crystal water content and thus reduces hydrogen bonding between amines. Moreover, we find that the stretched PEI chains on the surface of rambutan-like silica nanoparticles promote their binding capacity towards plasmid DNA molecules and thereby enhanced gene delivery and transfection efficiency. Our findings have provided new understanding about amine based polymers modified on nanoparticles, and have significant implications on the design of efficient particulate vectors for gene delivery.
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http://dx.doi.org/10.1039/d0tb00720jDOI Listing
June 2020

[email protected] Framework Core-Satellite Nanocomposites for the Serum Metabolic Fingerprinting of Gynecological Cancers.

Angew Chem Int Ed Engl 2020 06 7;59(27):10831-10835. Epub 2020 May 7.

School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200241, P. R. China.

High-throughput metabolic analysis is of significance in diagnostics, while tedious sample pretreatment has largely hindered its clinic application. Herein, we designed [email protected] composites with enhanced ionization efficiency and size-exclusion effect for laser desorption/ionization mass spectrometry (LDI-MS)-based metabolic diagnosis of gynecological cancers. The [email protected] LDI-MS achieved rapid, sensitive, and selective metabolic fingerprints of the native serum without any enrichment or purification. Further analysis of extracted serum metabolic fingerprints successfully discriminated patients with gynecological cancers (GCs) from healthy controls and also differentiated three major subtypes of GCs. Given the low cost, high-throughput, and easy operation, our approach brings a new dimension to disease analysis and classification.
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http://dx.doi.org/10.1002/anie.202001135DOI Listing
June 2020

Bottom-up self-assembly of heterotrimeric nanoparticles and their secondary Janus generations.

Chem Sci 2019 Nov 19;10(44):10388-10394. Epub 2019 Sep 19.

Australian Institute for Bioengineering and Nanotechnology , The University of Queensland , St Lucia , Brisbane , QLD 4072 , Australia . Email: ; Email:

A bottom-up self-assembly approach is developed for the synthesis of type heterotrimeric nanoparticles, which can be converted into secondary Janus-type silica derivatives. Compared to spherical ones, Janus silica nanoparticles stimulate stronger phagocytosis and transcytosis through intestinal epithelial microfold cells and exhibit higher cargo transport across an epithelial monolayer model mimicking the human intestinal epithelium.
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http://dx.doi.org/10.1039/c9sc02961cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988604PMC
November 2019

Functional Nanoparticles with a Reducible Tetrasulfide Motif to Upregulate mRNA Translation and Enhance Transfection in Hard-to-Transfect Cells.

Angew Chem Int Ed Engl 2020 02 9;59(7):2695-2699. Epub 2020 Jan 9.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, 4072, Australia.

Effective messenger RNA (mRNA) transfection in hard-to-transfect cells delivered by vectors is a long-standing challenge. Now it is hypothesized that the high intracellular glutathione level is associated with suppressed mRNA translation. This theory leads to a new design principle of next-generation mRNA vectors: nanoparticles with glutathione depletion chemistry upregulate mRNA translation and enhance transfection, which is beneficial for mRNA delivery in hard-to-transfect cells in vitro and in vivo.
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http://dx.doi.org/10.1002/anie.201914264DOI Listing
February 2020

Antibiotic-Free Antibacterial Strategies Enabled by Nanomaterials: Progress and Perspectives.

Adv Mater 2020 May 3;32(18):e1904106. Epub 2019 Dec 3.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, 4072, Australia.

Bacterial infection is one of the top ten leading causes of death globally and the worst killer in low-income countries. The overuse of antibiotics leads to ever-increasing antibiotic resistance, posing a severe threat to human health. Recent advances in nanotechnology provide new opportunities to address the challenges in bacterial infection by killing germs without using antibiotics. Antibiotic-free antibacterial strategies enabled by advanced nanomaterials are presented. Nanomaterials are classified on the basis of their mode of action: nanomaterials with intrinsic or light-mediated bactericidal properties and others that serve as vehicles for the delivery of natural antibacterial compounds. Specific attention is given to antibacterial mechanisms and the structure-performance relationship. Practical antibacterial applications employing these antibiotic-free strategies are also introduced. Current challenges in this field and future perspectives are presented to stimulate new technologies and their translation to fight against bacterial infection.
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http://dx.doi.org/10.1002/adma.201904106DOI Listing
May 2020

Responsively Aggregatable Sub-6 nm Nanochelators Induce Simultaneous Antiangiogenesis and Vascular Obstruction for Enhanced Tumor Vasculature Targeted Therapy.

Nano Lett 2019 11 30;19(11):7750-7759. Epub 2019 Oct 30.

Australian Institute for Bioengineering and Nanotechnology , The University of Queensland , St. Lucia , Brisbane , Queensland 4072 , Australia.

Inhibiting the formation of new tumor blood vessels (so-called antiangiogenesis) and obstructing the established ones are two primary strategies in tumor vasculature targeted therapy. However, the therapeutic outcome of conventional methodologies relying on only one mechanism is rather limited. Herein, the first example of ultrasmall responsively aggregatable nanochelators that can intrinsically fulfill both antivasculature functions as well as high renal clearable efficiency is introduced. The nanochelators with sub-6 nm sizes exhibit not only systemic copper depletion activity for tumor antiangiogenesis but also, more surprisingly, the capability to transform from a "dispersed" state to an "aggregated" state to form large secondary particles in response to tumor microenvironment with elevated copper and phosphate levels for blood vessel obstruction. Compared to a benchmark antiangiogenic agent that can only inhibit the formation of tumor blood vessels, the nanochelators with unprecedented synergistic functions demonstrate significantly enhanced tumor inhibition activity in both breast cancer and colon cancer tumor models. Moreover, these ultrasmall nanochelators are noncytotoxic and renal clearable, ensuring superior biocompatibility. It is envisaged that the design of nanomaterials with ground-breaking properties and the synergistic antivasculature functions would offer a substantial conceptual advance for tumor vasculature targeted therapy and may provide vast opportunities for developing advanced nanomedicines.
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http://dx.doi.org/10.1021/acs.nanolett.9b02691DOI Listing
November 2019

Mechanism of Iron Oxide-Induced Macrophage Activation: The Impact of Composition and the Underlying Signaling Pathway.

J Am Chem Soc 2019 04 4;141(15):6122-6126. Epub 2019 Apr 4.

Australian Institute for Bioengineering and Nanotechnology , The University of Queensland , Brisbane , QLD 4072 , Australia.

Iron oxide nanoparticles (IONPs) have emerging anticancer applications via polarizing tumor-associated macrophages from tumor-promoting phenotype (M2) to tumor-suppressing phenotype (M1). However, the underlying mechanism and structure-function relationship remain unclear. We report magnetite IONPs are more effective compared to hematite in M1 polarization and tumor suppression. Moreover, magnetite IONPs specifically rely on interferon regulatory factor 5 signaling pathway for M1 polarization and down-regulate M2-assoicated arginase-1. This study provides new understandings and paves the way for designing advanced iron-based anticancer technologies.
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http://dx.doi.org/10.1021/jacs.8b10904DOI Listing
April 2019

Electron Tomography: A Unique Tool Solving Intricate Hollow Nanostructures.

Adv Mater 2019 Sep 30;31(38):e1801564. Epub 2018 Aug 30.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, 4072, Australia.

Innovations in nanofabrication have expedited advances in hollow-structured nanomaterials with increasing complexity, which, at the same time, set challenges for the precise determination of their intriguing and complicated 3D configurations. Conventional transmission electron microscopy (TEM) analysis typically yields 2D projections of 3D objects, which in some cases is insufficient to reflect the genuine architectures of these 3D nano-objects, providing misleading information. Advanced analytical approaches such as focused ion beam (FIB) and ultramicrotomy enable the real slicing of nanomaterials, realizing the direct observation of inner structures but with limited spatial discrimination. Electron tomography (ET) is a technique that retrieves spatial information from a series of 2D electron projections at different tilt angles. As a unique and powerful tool kit, this technique has experienced great advances in its application in materials science, resolving the intricate 3D nanostructures. Here, the exceptional capability of the ET technique in the structural, chemical, and quantitative analysis of hollow-structured nanomaterials is discussed in detail. The distinct information derived from ET analysis is highlighted and compared with conventional analysis methods. Along with the advances in microscopy technologies, the state-of-the-art ET technique offers great opportunities and promise in the development of hollow nanomaterials.
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http://dx.doi.org/10.1002/adma.201801564DOI Listing
September 2019

Hybrid Nanoreactors: Enabling an Off-the-Shelf Strategy for Concurrently Enhanced Chemo-immunotherapy.

Angew Chem Int Ed Engl 2018 09 6;57(36):11764-11769. Epub 2018 Aug 6.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia.

Immunosuppressive tumors generally exhibit poor response to immune checkpoint blockade based cancer immunotherapy. Rationally designed hybrid nanoreactors are now presented that have integrated functions as Fenton catalysts and glutathione depletion agents for amplifying the immunogenic cell death and activating immune cells. A simple physical mixture of nanoreactors and chemodrugs in combination with immune checkpoint blockades show synergistically and concurrently enhanced chemo-immunotherapy efficacy, inhibiting the growth of both treated primary immunosuppressive tumors and untreated distant tumors. The off-the-shelf strategy uses tumor antigens generated in situ and avoids cargo loading, and is thus a substantial advance in personalized nanomedicine for clinical translation.
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http://dx.doi.org/10.1002/anie.201807595DOI Listing
September 2018

Room temperature synthesis of dendritic mesoporous silica nanoparticles with small sizes and enhanced mRNA delivery performance.

J Mater Chem B 2018 Jun 4;6(24):4089-4095. Epub 2018 Jun 4.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia.

Dendritic mesoporous silica nanoparticles (DMSNs) with a small diameter (∼50 nm) and a large pore size (>20 nm) have been synthesized at room temperature. It is shown that the choice of room temperature synthesis favours the formation of large-pore and small-size DMSNs compared to conventional synthesis at higher temperature. Compared to mesoporous silica nanoparticles with a similar particle size but a smaller mesopore size and DMSNs with a similar pore size but a larger particle size, DMSNs with both a small particle size and a large pore size possess a higher in vitro mRNA transfection efficiency, indicating their potential as promising delivery vehicles for exogenous genetic molecules.
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http://dx.doi.org/10.1039/c8tb00544cDOI Listing
June 2018

Solvothermal-assisted evaporation-induced self-assembly of ordered mesoporous alumina with improved performance.

J Colloid Interface Sci 2018 Nov 15;529:432-443. Epub 2018 Jun 15.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane 4072, Australia. Electronic address:

A solvothermal-assisted evaporation-induced self-assembly (SA-EISA) approach has been developed for the synthesis of ordered mesoporous alumina (OMA) materials with high thermal stability and improved performance in catalysis. In conventional EISA process, the evaporation step is accompanied by the hydrolysis of organic aluminum precursors, thus the evaporation conditions have significant influences on the reaction and the final structure of OMA. In our approach, the solvothermal treatment step promotes the complete hydrolysis of aluminum precursors and produces partially condensed cluster-like aluminum hydroxyl species, which allows the formation of OMA in a broad range of evaporation conditions. Compared to mesoporous alumina obtained by conventional EISA process, OMA materials prepared by SA-EISA approach exhibit higher specific surface area, pore volume and thermal stability. When used as supporting materials for vanadium oxide catalyst, OMA materials obtained by the SA-EISA approach exhibit excellent activity, selectivity and stability for ethylbenzene dehydrogenation with carbon dioxide as a mild oxidant. Our contribution has provided new understanding in the synthesis of OMA materials with improved performance for catalytic applications.
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http://dx.doi.org/10.1016/j.jcis.2018.06.031DOI Listing
November 2018

Nano-resoles-Enabled Elegant Nanostructured Materials.

Chemistry 2018 Oct 11;24(55):14598-14607. Epub 2018 Jul 11.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia.

Since the extension of the Stöber method traditionally used in the synthesis of silica nanoparticles into the fabrication of resorcinol-formaldehyde nanospheres in 2011, significant progresses have been achieved in this exiting area of nano-resole-enabled synthesis of elegant nanostructures with versatile compositions and promising applications in various fields. To date, there are few reviews focused on this topic. In this minireview, we aim to provide an overview on recent developments, with the emphasis on nano-resoles as an enabling strategy in the synthesis of innovative materials. The history of nano-resoles and their distinct roles classified into four functions will be introduced. Clear understanding into this research field is vital for achieving rational design and controllable synthesis of a new generation of nano-resoles and their derived nanostructures.
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http://dx.doi.org/10.1002/chem.201802136DOI Listing
October 2018

Glutathione-depletion mesoporous organosilica nanoparticles as a self-adjuvant and Co-delivery platform for enhanced cancer immunotherapy.

Biomaterials 2018 08 17;175:82-92. Epub 2018 May 17.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address:

Silica based nanoparticles have emerged as a promising vaccine delivery system for cancer immunotherapy, but their bio-degradability, adjuvanticity and the resultant antitumor activity remain to be largely improved. In this study, we report biodegradable glutathione-depletion dendritic mesoporous organosilica nanoparticles (GDMON) with a tetrasulfide-incorporated framework as a novel co-delivery platform in cancer immunotherapy. Functionalized GDMON are capable of co-delivering an antigen protein (ovalbumin) and a toll-like receptor 9 (TLR9) agonist into antigen presenting cells (APCs) and inducing endosome escape. Moreover, decreasing the intracellular glutathione (GSH) level through the -S-S-/GSH redox chemistry increases the ROS generation level both in vitro and in vivo, facilitating cytotoxic T lymphocyte (CTL) proliferation and reducing tumour growth in an aggressive B16-OVA melanoma tumour model. Our results have shown the potential of GDMON as a novel self-adjuvant and co-delivery nanocarrier for cancer vaccine.
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http://dx.doi.org/10.1016/j.biomaterials.2018.05.025DOI Listing
August 2018

A Concentration-Dependent Insulin Immobilization Behavior of Alkyl-Modified Silica Vesicles: The Impact of Alkyl Chain Length.

Langmuir 2018 05 18;34(17):5011-5019. Epub 2018 Apr 18.

Australian Institute for Bioengineering and Nanotechnology , The University of Queensland , Brisbane , QLD 4072 , Australia.

The insulin immobilization behaviors of silica vesicles (SV) before and after modification with hydrophobic alkyl -C and -C groups have been studied and correlated to the grafted alkyl chain length. In order to minimize the influence from the other structural parameters, monolayered -C or -C groups are grafted onto SV with controlled density. The insulin immobilization capacity of SV is dependent on the initial insulin concentrations (IIC). At high IIC (2.6-3.0 mg/mL), the trend of insulin immobilization capacity of SV is SV-OH > SV-C > SV-C, which is determined mainly by the surface area of SV. At medium IIC (0.6-1.9 mg/mL), the trend changes to SV-C ≥ SV-C > SV-OH as both the surface area and alkyl chain length contribute to the insulin immobilization. At an extremely low IIC, the hydrophobic-hydrophobic interaction between the alkyl group and insulin molecules plays the most significant role. Consequently, SV-C with longer alkyl groups and the highest hydrophobicity show the best insulin enrichment performance compared to SV-C and SV-OH, as evidenced by an insulin detection limit of 0.001 ng/mL in phosphate buffered saline (PBS) and 0.05 ng/mL in artficial urine determined by mass spectrometry (MS).
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http://dx.doi.org/10.1021/acs.langmuir.8b00377DOI Listing
May 2018

Asymmetric mesoporous silica nanoparticles as potent and safe immunoadjuvants provoke high immune responses.

Chem Commun (Camb) 2018 Feb;54(16):2020-2023

Australian Institute of Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD-4072, Australia.

Asymmetric mesoporous silica nanoparticles with a head-tail structure are potent immunoadjuvants for delivering a peptide antigen, generating a higher antibody immune response in mice compared to their symmetric counterparts.
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http://dx.doi.org/10.1039/c8cc00327kDOI Listing
February 2018

Plasmid DNA Delivery: Nanotopography Matters.

J Am Chem Soc 2017 12 1;139(50):18247-18254. Epub 2017 Dec 1.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland , Brisbane, Queensland 4072, Australia.

Plasmid DNA molecules with unique loop structures have widespread bioapplications, in many cases relying heavily on delivery vehicles to introduce them into cells and achieve their functions. Herein, we demonstrate that control over delicate nanotopography of silica nanoparticles as plasmid DNA vectors has significant impact on the transfection efficacy. For silica nanoparticles with rambutan-, raspberry-, and flower-like morphologies composed of spike-, hemisphere-, and bowl-type subunit nanotopographies, respectively, the rambutan-like nanoparticles with spiky surfaces demonstrate the highest plasmid DNA binding capability and transfection efficacy of 88%, higher than those reported for silica-based nanovectors. Moreover, it is shown that the surface spikes of rambutan nanoparticles provide a continuous open space to bind DNA chains via multivalent interactions and protect the gene molecules sheltered in the spiky layer against nuclease degradation, exhibiting no significant transfection decay. This unique protection feature is in great contrast to a commercial transfection agent with similar transfection performance but poor protection capability against enzymatic cleavage. Our study provides new understandings in the rational design of nonviral vectors for efficient gene delivery.
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http://dx.doi.org/10.1021/jacs.7b08974DOI Listing
December 2017
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