Publications by authors named "Zhaowei Chen"

86 Publications

Gaseous Plastron on Natural and Biomimetic Surfaces for Resisting Marine Biofouling.

Molecules 2021 Apr 29;26(9). Epub 2021 Apr 29.

Institute of Food Safety and Environment Monitoring, College of Chemistry, Fuzhou University, Fuzhou 350108, China.

In recent years, various biomimetic materials capable of forming gaseous plastron on their surfaces have been fabricated and widely used in various disciplines and fields. In particular, on submerged surfaces, gaseous plastron has been widely studied for antifouling applications due to its ecological and economic advantages. Gaseous plastron can be formed on the surfaces of various natural living things, including plants, insects, and animals. Gaseous plastron has shown inherent anti-biofouling properties, which has inspired the development of novel theories and strategies toward resisting biofouling formation on different surfaces. In this review, we focused on the research progress of gaseous plastron and its antifouling applications.
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http://dx.doi.org/10.3390/molecules26092592DOI Listing
April 2021

Cytosolic Delivery of Thiolated Mn-cGAMP Nanovaccine to Enhance the Antitumor Immune Responses.

Small 2021 Apr 14;17(17):e2006970. Epub 2021 Mar 14.

MOE Key Laboratory for Analytical Science of Food Safety and Biology, State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, 350116, P. R. China.

As a stimulator of interferon gene (STING), cyclic dinucleotide activates a broad cellular immune response for anti-cancer immunotherapy (CIT). However, the inherent of instability of 2' 3'-cyclic-GMP-AMP (cGAMP) with poor cellular targeting, rapid clearance, and inefficient transport to the cytoplasm seriously hinders cGAMP potency. Here, a thiolated and Mn coordinated cyclic dinucleotide nanovaccine (termed as Mn-cGAMP NVs) to enable direct cytosolic co-delivery of cGAMP and Mn to potentiate the antitumor immune response is presented. In the NVs, the fixation cGAMP with Mn ions not only improve its stability, but also potentiate the activation of STING. Meanwhile, the presence of polysulfides on the NVs surface allowed direct cytosolic delivery while avoiding degradation. In this way, the production of cytokines for activating T cells immunity is greatly elevated, which in turn suppressed the primary and distal tumors growth through long-term immune memory and led to long-term survival of poorly immunogenic B16F10 melanoma mice. Moreover, by further combining with anti-PD-L1 monoclonal antibody, synergistic T cells antitumor immune response is elicited. This work offers a promising strategy to enhance the potency of cGAMP, holding a considerable potential for CIT applications.
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http://dx.doi.org/10.1002/smll.202006970DOI Listing
April 2021

Loss of sarcomeric proteins via upregulation of JAK/STAT signaling underlies interferon-γ-induced contractile deficit in engineered human myocardium.

Acta Biomater 2021 05 8;126:144-153. Epub 2021 Mar 8.

Department of Biomedical Engineering, Duke University, 101 Science Drive, Durham, NC 27708, USA. Electronic address:

The level of circulating interferon-γ (IFNγ) is elevated in various clinical conditions including autoimmune and inflammatory diseases, sepsis, acute coronary syndrome, and viral infections. As these conditions are associated with high risk of myocardial dysfunction, we investigated the effects of IFNγ on 3D fibrin-based engineered human cardiac tissues ("cardiobundles"). Cardiobundles were fabricated from human pluripotent stem cell-derived cardiomyocytes, exposed to 0-20 ng/ml of IFNγ on culture days 7-14, and assessed for changes in tissue structure, viability, contractile force and calcium transient generation, action potential propagation, cytokine secretion, and expression of select genes and proteins. We found that application of IFNγ induced a dose-dependent reduction in contractile force generation, deterioration of sarcomeric organization, and cardiomyocyte disarray, without significantly altering cell viability, action potential propagation, or calcium transient amplitude. At molecular level, the IFNγ-induced structural and functional deficits could be attributed to altered balance of pro- and anti-inflammatory cytokines, upregulation of JAK/STAT signaling pathway (JAK1, JAK2, and STAT1), and reduced expression of myosin heavy chain, myosin light chain-2v, and sarcomeric α-actinin. Application of clinically used JAK/STAT inhibitors, tofacitinib and baricitinib, fully prevented IFNγ-induced cardiomyopathy, confirming the critical roles of this signaling pathway in inflammatory cardiac disease. Taken together, our in vitro studies in engineered myocardial tissues reveal direct adverse effects of pro-inflammatory cytokine IFNγ on human cardiomyocytes and establish the foundation for a potential use of cardiobundle platform in modeling of inflammatory myocardial disease and therapy. STATEMENT OF SIGNIFICANCE: Various inflammatory and autoimmune diseases including rheumatoid arthritis, sepsis, lupus erythematosus, Chagas disease, and others, as well as viral infections including H1N1 influenza and COVID-19 show increased systemic levels of a pro-inflammatory cytokine interferon-γ (IFNγ) and are associated with high risk of heart disease. Here we explored for the first time if chronically elevated levels of IFNγ can negatively affect structure and function of engineered human heart tissues in vitro. Our studies revealed IFNγ-induced deterioration of myofibrillar organization and contractile force production in human cardiomyocytes, attributed to decreased expression of multiple sarcomeric proteins and upregulation of JAK/STAT signaling pathway. FDA-approved JAK inhibitors fully blocked the adverse effects of IFNγ, suggesting a potentially effective strategy against human inflammatory cardiomyopathy.
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http://dx.doi.org/10.1016/j.actbio.2021.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096718PMC
May 2021

Wireless Optogenetic Modulation of Cortical Neurons Enabled by Radioluminescent Nanoparticles.

ACS Nano 2021 03 24;15(3):5201-5208. Epub 2021 Feb 24.

Center for Nanoscale Materials, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, Illinois 60439, United States.

While offering high-precision control of neural circuits, optogenetics is hampered by the necessity to implant fiber-optic waveguides in order to deliver photons to genetically engineered light-gated neurons in the brain. Unlike laser light, X-rays freely pass biological barriers. Here we show that radioluminescent Gd(WO):Eu nanoparticles, which absorb external X-rays energy and then downconvert it into optical photons with wavelengths of ∼610 nm, can be used for the transcranial stimulation of cortical neurons expressing red-shifted, ∼590-630 nm, channelrhodopsin ReaChR, thereby promoting optogenetic neural control to the practical implementation of minimally invasive wireless deep brain stimulation.
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http://dx.doi.org/10.1021/acsnano.0c10436DOI Listing
March 2021

Fast Stereolithography Printing of Large-Scale Biocompatible Hydrogel Models.

Adv Healthc Mater 2021 Feb 15:e2002103. Epub 2021 Feb 15.

Department of Biomedical Engineering, University at Buffalo, The State University of New York, Buffalo, NY, 14260, USA.

Large size cell-laden hydrogel models hold great promise for tissue repair and organ transplantation, but their fabrication using 3D bioprinting is limited by the slow printing speed that can affect the part quality and the biological activity of the encapsulated cells. Here a fast hydrogel stereolithography printing (FLOAT) method is presented that allows the creation of a centimeter-sized, multiscale solid hydrogel model within minutes. Through precisely controlling the photopolymerization condition, low suction force-driven, high-velocity flow of the hydrogel prepolymer is established that supports the continuous replenishment of the prepolymer solution below the curing part and the nonstop part growth. The rapid printing of centimeter-sized hydrogel models using FLOAT is shown to significantly reduce the part deformation and cellular injury caused by the prolonged exposure to the environmental stresses in conventional 3D printing methods. Embedded vessel networks fabricated through multiscale printing allows media perfusion needed to maintain the high cellular viability and metabolic functions in the deep core of the large-sized models. The endothelialization of this vessel network allows the establishment of barrier functions. Together, these studies demonstrate a rapid 3D hydrogel printing method and represent a first step toward the fabrication of large-sized engineered tissue models.
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http://dx.doi.org/10.1002/adhm.202002103DOI Listing
February 2021

Topographical nanostructures for physical sterilization.

Drug Deliv Transl Res 2021 Feb 4. Epub 2021 Feb 4.

College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, People's Republic of China.

The development in nanobiotechnology provides an in-depth understanding of cell-surface interactions at the nanoscale level. Particularly, several surface features have shown the ability to interrogate the bacterial behavior and fate. In the past decade, the mechanical and physical sterilization has attracted considerable attention, as paradigms of such do not rely on chemical substances to damage or kill bacteria, whereas it is associated with natural living organisms or synthetic materials. Of note, such antibacterial scenario does not cause bacterial resistance, as the morphology of nanometer can directly cause bacterial death through physical and mechanical interactions. In this review, we provide an overview of recently developed technologies of leveraging topographical nanofeatures for physical sterilization. We mainly discuss the development of various morphologic nanostructures, and colloidal nanostructures show casing the capacity of "mechanical sterilization." Mechanically sterilized nanostructures can penetrate or cut through bacterial membranes. In addition, surface morphology, such as mechanical bactericidal nanoparticles and nanoneedles, can cause damage to the membrane of microorganisms, leading to cell lysis and death. Although the research in the field of mechanical sterilization is still in infancy, the effect of these nanostructure morphologies on sterilization has shown remarkable antibacterial potential, which could provide a new toolkit for anti-infection and antifouling applications. The mechanical and physical sterilization has attracted considerable attention, as paradigms of such do not rely on chemical substances to damage or kill bacteria. Moreover, such antibacterial scenario does not cause bacterial resistance, as the morphology of nanometer can directly cause bacterial death through physical and mechanical interactions. In this review, we focus on the advanced development of various morphologic nanostructures and colloidal nanostructures that show the capacity of "mechanical sterilization."
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http://dx.doi.org/10.1007/s13346-021-00906-9DOI Listing
February 2021

Exercise mimetics and JAK inhibition attenuate IFN-γ-induced wasting in engineered human skeletal muscle.

Sci Adv 2021 Jan 22;7(4). Epub 2021 Jan 22.

Department of Biomedical Engineering, Duke University, Durham, NC, USA.

Chronic inflammatory diseases often lead to muscle wasting and contractile deficit. While exercise can have anti-inflammatory effects, the underlying mechanisms remain unclear. Here, we used an in vitro tissue-engineered model of human skeletal muscle ("myobundle") to study effects of exercise-mimetic electrical stimulation (E-stim) on interferon-γ (IFN-γ)-induced muscle weakness. Chronic IFN-γ treatment of myobundles derived from multiple donors induced myofiber atrophy and contractile loss. E-stim altered the myobundle secretome, induced myofiber hypertrophy, and attenuated the IFN-γ-induced myobundle wasting and weakness, in part by down-regulating JAK (Janus kinase)/STAT1 (signal transducer and activator of transcription 1) signaling pathway amplified by IFN-γ. JAK/STAT inhibitors fully prevented IFN-γ-induced myopathy, confirming the critical roles of STAT1 activation in proinflammatory action of IFN-γ. Our results reveal a previously unknown mechanism of the cell-autonomous anti-inflammatory effects of muscle exercise and establish the utility of human myobundle platform for studies of inflammatory muscle disease and therapy.
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http://dx.doi.org/10.1126/sciadv.abd9502DOI Listing
January 2021

Synthesis Characterization of Platinum (IV) Complex Curcumin Backboned Polyprodrugs: In Vitro Drug Release Anticancer Activity.

Polymers (Basel) 2020 Dec 26;13(1). Epub 2020 Dec 26.

Institute of Food Safety and Environment Monitoring, College of Chemistry, Fuzhou University, Fuzhou 350108, China.

The conventional mono-chemotherapy still suffers from unsatisfied potency for cancer therapy due to tumor heterogeneity and the occurrence of drug resistance. Combination chemotherapy based on the nanosized drug delivery systems (nDDSs) has been developed as a promising platform to circumvent the limitations of mono-chemotherapy. In this work, starting from cisplatin and curcumin (Cur), we prepared a dual drug backboned shattering polymeric nDDS for synergistic chemotherapy. By in situ polymerization of the Cur, platinum (IV) complex-based prodrug monomer (DHP), L-lysine diisocyanate (LDI), and then conjugation with a hydrophilic poly (ethylene glycol) monomethyl ether (mPEG) derivative, a backbone-type platinum (IV) and Cur linkage containing mPEG-poly(platinum-co-Cur)-mPEG (PCPt) copolymer was synthesized. Notably, the platinum (IV) (Pt (IV)) and Cur were incorporated into the hydrophobic segment of PCPt with the fixed drugs loading ratio and high drugs loading content. The batch-to-batch variability could be decreased. The resulting prodrug copolymer then self-assembled into nanoparticles (PCPt NPs) with an average diameter around 100 nm, to formulate a synergetic nDDS. Importantly, PCPt NPs could greatly improve the solubility and stability of Cur. In vitro drug release profiles have demonstrated that PCPt NPs were stable in PBS 7.4, rapid burst release was greatly decreased, and the Pt and Cur release could be largely enhanced under reductive conditions due to the complete dissociation of the hydrophobic main chain of PCPt. In vitro cell viability test indicated that PCPt NPs were efficient synergistic chemotherapy units. Moreover, PCPt NPs were synergistic for cisplatin-resistant cell lines A549/DDP cells, and they exhibited excellent reversal ability of tumor resistance to cisplatin. This work provides a promising strategy for the design and synthesis of nDDS for combination chemotherapy.
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http://dx.doi.org/10.3390/polym13010067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795977PMC
December 2020

Photogenerated Holes Mediated Nitric Oxide Production for Hypoxic Tumor Treatment.

Angew Chem Int Ed Engl 2021 03 19;60(13):7046-7050. Epub 2021 Feb 19.

MOE Key Laboratory for Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection Technology for Food Safety, State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, 350108, P. R. China.

Nitric oxide (NO) is a gaseous signal molecule with multiple physiological functions, and it also plays a key role in cancer therapy. However, the production of NO which depends on O or H O is limited within the tumor microenvironment, leading to unsatisfactory anticancer effect. Herein, we report a NO-based phototherapeutic strategy mediated by photogenerated holes for hypoxic tumors, which is achieved by irradiation of the poly-L-arginine modified carbon-dots-doped graphitic carbon nitride nanomaterial (ArgCCN). Upon red light irradiation, the photogenerated holes on ArgCCN oxidized water into H O which subsequently oxidized the arginine residues to produce NO. In vitro and in vivo experiments showed that the high concentration of NO produced by ArgCCN could induce cancer cell apoptosis. The presented phototherapeutic strategy is based on microenvironment-independent photogenerated holes mediated oxidation reaction, paving the way for the development of NO therapeutic strategy.
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http://dx.doi.org/10.1002/anie.202015082DOI Listing
March 2021

Local and Targeted Delivery of Immune Checkpoint Blockade Therapeutics.

Acc Chem Res 2020 11 19;53(11):2521-2533. Epub 2020 Oct 19.

Department of Bioengineering, University of California, Los Angeles, California 90095, United States.

Immune checkpoint blockade (ICB) therapy elicits antitumor response by inhibiting immune suppressor components, including programmed cell death protein 1 and its ligand (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Despite improved therapeutic efficacy, the clinical response rate is still unsatisfactory as revealed by the fact that only a minority of patients experience durable benefits. Additionally, "off-target" effects after systemic administration remain challenging for ICB treatment. To this end, the local and targeted delivery of ICB agents instead could be a potential solution to maximize the therapeutic outcomes while minimizing the side effects.In this Account, our recent studies directed at the development of different strategies for the local and targeted delivery of ICB agents are discussed. For example, transdermal microneedle patches loaded with anti-programmed death-1 antibody (aPD1) and anti-CTLA4 were developed to facilitate sustained release of ICB agents at the diseased sites. Triggered release could also be achieved by various stimuli within the tumor microenvironment, including low pH and abnormally expressed enzymes. Recently, the combination of an anti-programmed death-ligand 1 antibody (aPD-L1) loaded hollow-structured microneedle patch with cold atmospheric plasma (CAP) therapy was also reported. Microneedles provided microchannels to facilitate the transdermal transport of CAP and further induce immunogenic tumor cell death, which could be synergized by the local release of aPD-L1. In addition, formed injectable or sprayable hydrogels were tailored to deliver immunomodulatory antibodies to the surgical bed to inhibit tumor recurrence after primary tumor resection. In paralell, inspired by the unique targeting ability of platelets toward the inflammatory sites, we engineered natural platelets decorated with aPD-L1 for targeted delivery after tumor resection to inhibit tumor recurrence. We further constructed a cell-cell combination delivery platform based on conjugates of platelets and hematopoietic stem cells (HSCs) for leukemia treatment. With the homing ability of HSCs to the bone marrow, the HSC-platelet-aPD1 assembly could effectively deliver aPD1 in an acute myeloid leukemia mouse model. Besides living cells, we also leveraged HEK293T-derived vesicles with PD1 receptors on their surfaces to disrupt the PD-1/PD-L1 immune inhibitory pathway. Moreover, the inner space of the vesicles allowed the packaging of an indoleamine 2,3-dioxygenase inhibitor, further reinforcing the therapeutic efficacy. A similar approach has also been demonstrated by genetically engineering platelets overexpressing PD1 receptor for postsurgical treatment. We hope the local and targeted ICB agent delivery methods introduced in this collection would further inspire the development of advanced drug delivery strategies to improve the efficiency of cancer treatment while alleviating side effects.
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http://dx.doi.org/10.1021/acs.accounts.0c00339DOI Listing
November 2020

Roadmap on nanomedicine.

Nanotechnology 2021 Jan;32(1):012001

Laboratory of Nanotechnology for Precision Medicine, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, Genoa 16163, Italy.

Since the launch of the Alliance for Nanotechnology in Cancer by the National Cancer Institute in late 2004, several similar initiatives have been promoted all over the globe with the intention of advancing the diagnosis, treatment and prevention of cancer in the wake of nanoscience and nanotechnology. All this has encouraged scientists with diverse backgrounds to team up with one another, learn from each other, and generate new knowledge at the interface between engineering, physics, chemistry and biomedical sciences. Importantly, this new knowledge has been wisely channeled towards the development of novel diagnostic, imaging and therapeutic nanosystems, many of which are currently at different stages of clinical development. This roadmap collects eight brief articles elaborating on the interaction of nanomedicines with human biology; the biomedical and clinical applications of nanomedicines; and the importance of patient stratification in the development of future nanomedicines. The first article reports on the role of geometry and mechanical properties in nanomedicine rational design; the second articulates on the interaction of nanomedicines with cells of the immune system; and the third deals with exploiting endogenous molecules, such as albumin, to carry therapeutic agents. The second group of articles highlights the successful application of nanomedicines in the treatment of cancer with the optimal delivery of nucleic acids, diabetes with the sustained and controlled release of insulin, stroke by using thrombolytic particles, and atherosclerosis with the development of targeted nanoparticles. Finally, the last contribution comments on how nanomedicine and theranostics could play a pivotal role in the development of personalized medicines. As this roadmap cannot cover the massive extent of development of nanomedicine over the past 15 years, only a few major achievements are highlighted as the field progressively matures from the initial hype to the consolidation phase.
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http://dx.doi.org/10.1088/1361-6528/abaadbDOI Listing
January 2021

Sirt6 deficiency aggravates angiotensin II-induced cholesterol accumulation and injury in podocytes.

Theranostics 2020 12;10(16):7465-7479. Epub 2020 Jun 12.

Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.

Disturbed renal lipid metabolism, especially cholesterol dysregulation plays a crucial role in the pathogenesis of chronic kidney disease (CKD). We recently reported that angiotensin (Ang) II could induce cholesterol accumulation and injury in podocytes. However, the underlying mechanisms for these alterations remain unknown. Bioinformatics analysis of renal biopsy specimens from patients with hypertensive nephropathy (HN) suggests the involvement of Sirtuin 6 (Sirt6) in Ang II-induced dysregulation of glomerular cholesterol. Using a podocyte-specific Sirt6 knockout mouse model, the effects of Sirt6 on Ang II-induced cholesterol accumulation in podocytes and the therapeutic efficacies of cholesterol-lowering agents were evaluated. Cholesterol accumulation was detected in the podocytes of Ang II-infused mice, whereas selective deletion of Sirt6 in podocytes not only increased cholesterol accumulation in these cells but also exacerbated Ang II-induced kidney injury. Deletion of Sirt6 also attenuated the protective effect of cyclodextrin (CD) on Ang II-induced urinary albumin excretion, glomerulosclerosis and podocyte injury. In addition, we demonstrated that Sirt6 affected cholesterol efflux in podocytes by regulating the expression of ATP-binding cassette transporter G1 (ABCG1). These findings provide evidence that Sirt6 is a potential target for renin-angiotensin system (RAS)-associated podocyte injury and provide a rationale for the application of cholesterol-lowering agents in patients with CKD.
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http://dx.doi.org/10.7150/thno.45003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330847PMC
May 2021

A negative feedback loop between JNK-associated leucine zipper protein and TGF-β1 regulates kidney fibrosis.

Commun Biol 2020 Jun 5;3(1):288. Epub 2020 Jun 5.

Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.

Renal fibrosis is controlled by profibrotic and antifibrotic forces. Exploring anti-fibrosis factors and mechanisms is an attractive strategy to prevent organ failure. Here we identified the JNK-associated leucine zipper protein (JLP) as a potential endogenous antifibrotic factor. JLP, predominantly expressed in renal tubular epithelial cells (TECs) in normal human or mouse kidneys, was downregulated in fibrotic kidneys. Jlp deficiency resulted in more severe renal fibrosis in unilateral ureteral obstruction (UUO) mice, while renal fibrosis resistance was observed in TECs-specific transgenic Jlp mice. JLP executes its protective role in renal fibrosis via negatively regulating TGF-β1 expression and autophagy, and the profibrotic effects of ECM production, epithelial-to-mesenchymal transition (EMT), apoptosis and cell cycle arrest in TECs. We further found that TGF-β1 and FGF-2 could negatively regulate the expression of JLP. Our study suggests that JLP plays a central role in renal fibrosis via its negative crosstalk with the profibrotic factor, TGF-β1.
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http://dx.doi.org/10.1038/s42003-020-1008-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275040PMC
June 2020

Sestrin‑2 regulates podocyte mitochondrial dysfunction and apoptosis under high‑glucose conditions via AMPK.

Int J Mol Med 2020 May 20;45(5):1361-1372. Epub 2020 Feb 20.

Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.

Diabetic kidney disease (DKD) is a severe form of microangiopathy among diabetic patients, of which podocyte injury is one of the more predominant features. There is increasing evidence to suggest that mitochondrial dysfunction is associated with podocyte injury, thus contributing to the progression of DKD. Initially identified as a p53 target protein, the endogenous antioxidant protein, sestrin‑2 (sesn2), has recently attracted attention due to its potential function in various inflammatory diseases. However, the association between sesn2 and podocytes in DKD remains unclear. In the present study, to elucidate the role of sesn2 in podocyte mitochondrial dysfunction, the effects of sesn2 on the regulation of AMP‑activated protein kinase (AMPK) were examined in vitro and in vivo. Abnormal mitochondria were found in rats with streptozotocin‑induced diabetes, and hyperglycemia downregulated the expression of sesn2. The upregulation of sesn2 increased the level of AMPK phosphorylation, and thus ameliorated mitochondrial dysfunction under high glucose conditions (HG). On the whole, these results suggest that sesn2 is associated with mitochondrial dysfunction in podocytes under HG conditions. In addition, the decreased expression of sesn2 may be a therapeutic target for DKD.
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http://dx.doi.org/10.3892/ijmm.2020.4508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138269PMC
May 2020

Cargo-encapsulated cells for drug delivery.

Sci China Life Sci 2020 Apr 5;63(4):599-601. Epub 2020 Mar 5.

Department of Bioengineering, University of California, Los Angeles, CA, 90095, USA.

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http://dx.doi.org/10.1007/s11427-020-1653-yDOI Listing
April 2020

AKAP1 mediates high glucose-induced mitochondrial fission through the phosphorylation of Drp1 in podocytes.

J Cell Physiol 2020 10 28;235(10):7433-7448. Epub 2020 Feb 28.

Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.

Increasing evidence suggests that mitochondrial dysfunction plays a critical role in the development of diabetic kidney disease (DKD), however, its specific pathomechanism remains unclear. A-kinase anchoring protein (AKAP) 1 is a scaffold protein in the AKAP family that is involved in mitochondrial fission and fusion. Here, we show that rats with streptozotocin (STZ)-induced diabetes developed podocyte damage accompanied by AKAP1 overexpression and that AKAP1 closely interacted with the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). At the molecular level, high glucose (HG) promoted podocyte injury and Drp1 phosphorylation at Ser637 as proven by decreased mitochondrial membrane potential, elevated reactive oxygen species generation, reduced adenosine triphosphate synthesis, and increased podocyte apoptosis. Furthermore, the AKAP1 knockdown protected HG-induced podocyte injury and suppressed HG-induced Drp1 phosphorylation at Ser637. AKAP1 overexpression aggravated HG-induced mitochondrial fragmentation and podocyte apoptosis. The coimmunoprecipitation assay showed that HG-induced Drp1 interacted with AKAP1, revealing that AKAP1 could recruit Drp1 from the cytoplasm under HG stimulation. Subsequently, we detected the effect of drp1 phosphorylation on Ser637 by transferring several different Drp1 mutants. We demonstrated that activated AKAP1 promoted Drp1 phosphorylation at Ser637, which promoted the transposition of Drp1 to the surface of the mitochondria and accounts for mitochondrial dysfunction events. These findings indicate that AKAP1 is the main pathogenic factor in the development and progression of HG-induced podocyte injury through the destruction of mitochondrial dynamic homeostasis by regulating Drp1 phosphorylation in human podocytes.
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http://dx.doi.org/10.1002/jcp.29646DOI Listing
October 2020

Transdermal colorimetric patch for hyperglycemia sensing in diabetic mice.

Biomaterials 2020 04 13;237:119782. Epub 2020 Jan 13.

Department of Bioengineering, University of California, Los Angeles, CA, 90095, United States; California NanoSystems Institute, University of California, Los Angeles, CA, 90095, United States; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, 90095, United States; Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA, 90095, United States. Electronic address:

The integration of sampling and instant metabolite readout can fundamentally elevate patient compliance. To circumvent the need for complex in-lab apparatus, here, an all-in-one sampling and display transdermal colorimetric microneedle patch was developed for sensing hyperglycemia in mice. The coloration of 3,3',5,5'-tetramethylbenzidine (TMB) is triggered by the cascade enzymatic reactions of glucose oxidase (GOx) and horseradish peroxidase (HRP) at abnormally high glucose levels. The HRP in the upper layer is biomineralized with calcium phosphate (CaP) shell to add a pH responsive feature for increased sensitivity as well as protection from nonspecific reactions. This colorimetric sensor achieved minimally invasive extraction of the interstitial fluid from mice and converted glucose level to a visible color change promptly. Quantitative red green and blue (RGB) information could be obtained through a scanned image of the microneedle. This costless, portable colorimetric sensor could potentially detect daily glucose levels without blood drawing procedures.
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http://dx.doi.org/10.1016/j.biomaterials.2020.119782DOI Listing
April 2020

Corrigendum to "Activation of biologically relevant levels of reactive oxygen species by Au/g-CN hybrid nanozyme for bacteria killing and wound disinfection" [Biomaterials, 113(2017)145-157].

Biomaterials 2020 Mar 9;233:119754. Epub 2020 Jan 9.

Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resources Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, PR China. Electronic address:

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http://dx.doi.org/10.1016/j.biomaterials.2019.119754DOI Listing
March 2020

Advances in nanomedicine for cancer starvation therapy.

Theranostics 2019 17;9(26):8026-8047. Epub 2019 Oct 17.

Department of Bioengineering, Jonsson Comprehensive Cancer Center, California Nanosystems Institute (CNSI), and Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA 90095, USA.

Abnormal cell metabolism with vigorous nutrition consumption is one of the major physiological characteristics of cancers. As such, the strategy of cancer starvation therapy through blocking the blood supply, depleting glucose/oxygen and other critical nutrients of tumors has been widely studied to be an attractive way for cancer treatment. However, several undesirable properties of these agents, such as low targeting efficacy, undesired systemic side effects, elevated tumor hypoxia, induced drug resistance, and increased tumor metastasis risk, limit their future applications. The recent development of starving-nanotherapeutics combined with other therapeutic methods displayed the promising potential for overcoming the above drawbacks. This review highlights the recent advances of nanotherapeutic-based cancer starvation therapy and discusses the challenges and future prospects of these anticancer strategies.
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http://dx.doi.org/10.7150/thno.38261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857045PMC
September 2020

HIF-1α contributes to Ang II-induced inflammatory cytokine production in podocytes.

BMC Pharmacol Toxicol 2019 10 17;20(1):59. Epub 2019 Oct 17.

Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.

Background: Studies have indicated that changed expression of hypoxia-inducible factor-1α (HIF-1α) in epithelial cells from the kidney could affect the renal function in chronic kidney disease (CKD). As Angiotensin II (Ang II) is a critical active effector in the renin-angiotensin system (RAS) and was proved to be closely related to the inflammatory injury. Meanwhile, researchers found that Ang II could alter the expression of HIF-1α in the kidney. However, whether HIF-1α is involved in mediating Ang II-induced inflammatory injury in podocytes is not clear.

Methods: Ang II perfusion animal model were established to assess the potential role of HIF-1α in renal injury in vivo. Ang II stimulated podocytes to observe the corresponding between HIF-1α and inflammatory factors in vitro.

Results: The expression of inflammatory cytokines such as MCP-1 and TNF-α was increased in the glomeruli from rats treated with Ang II infusion compared with control rats. Increased HIF-1α expression in the glomeruli was also observed in Ang II-infused rats. In vitro, Ang II upregulated the expression of HIF-1α in podocytes. Furthermore, knockdown of HIF-1α by siRNA decreased the expression of MCP-1 and TNF-α. Moreover, HIF-1α siRNA significantly diminished the Ang II-induced overexpression of HIF-1α.

Conclusion: Collectively, our results suggest that HIF-1α participates in the inflammatory response process caused by Ang II and that downregulation of HIF-1α may be able to partially protect or reverse inflammatory injury in podocytes.
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http://dx.doi.org/10.1186/s40360-019-0340-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796393PMC
October 2019

Mitochondrial pyruvate carrier 2 mediates mitochondrial dysfunction and apoptosis in high glucose-treated podocytes.

Life Sci 2019 Nov 10;237:116941. Epub 2019 Oct 10.

Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China. Electronic address:

Aims: Podocytes play an important role in the development of diabetic kidney disease (DKD). Mitochondria are the source of energy for cell survival, and mitochondrial abnormalities have been shown to contribute to podocyte injury in DKD. In high glucose (HG)-treated podocytes, mitochondrial function and dynamics are abnormal, and intracellular metabolism is often disrupted. However, the molecular mechanism is still unclear. Mitochondrial pyruvate carrier 2 (MPC2) mediates pyruvate transport from the cytoplasm to the mitochondrial matrix, which determines the cellular energy supply and cell survival. Here, we hypothesize that MPC2 damages mitochondria and induces apoptosis in HG-treated podocytes.

Main Methods: We used Western blotting, immunofluorescence and immunoprecipitation to detect the expression of MPC2 in HG-treated podocytes. Pyruvate levels were measured to evaluate metabolic station. Mitochondrial membrane potential (MMP) was measured by inverted fluorescence microscopy and flow cytometry. Mitochondrial morphology was assayed by MitoTracker Red staining, and cellular apoptosis was examined by flow cytometry. Furthermore, we treated podocytes with UK5099 and MPC2 siRNA to assess the outcomes of UK5099 treatment and MPC2 knockdown.

Key Findings: Intracellular pyruvate accumulated, the mitochondria were damaged and cellular apoptosis increased in podocytes cultured with HG compared to that in control podocytes. MPC2 acetylation was significantly increased in HG-treated podocytes. Furthermore, the mitochondrial morphology changed, the MMP decreased, and cellular apoptosis increased. Inhibition of MPC2 function by UK5099 or MPC2 knockdown by siRNA produced the same abnormal effects observed following treatment with HG.

Significance: MPC2 may mediate mitochondrial dysfunction in HG-treated podocytes, ultimately leading to cell apoptosis.
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http://dx.doi.org/10.1016/j.lfs.2019.116941DOI Listing
November 2019

Promoting Noncovalent Intermolecular Interactions Using a C Core Particle in Aqueous PC60s-Covered Colloids for Ultraefficient Photoinduced Particle Activity.

ACS Appl Mater Interfaces 2019 Oct 11;11(42):38798-38807. Epub 2019 Oct 11.

Center for Nanoscale Materials , Argonne National Laboratory , Lemont , Illinois 60439 , United States.

Noncovalent intermolecular interactions in nanomaterials, such as van der Waals effects, allow adjustment of the nanoscopic size of compounds and their conformation in molecular crystal regimes. These strong interactions permit small particle sizes to be maintained as the crystals grow. In particular, these effects can be leveraged in the confined/reinforcing phase of molecules. With this in mind, we used C molecules as a core particle in single-PC60 surfactant-covered colloid in a water-processable system. Compared with our previous results based on a PCBM core-PC60 shell particle, the PC60-C colloid had a considerably smaller spherical structure due to the increased intermolecular interactions between C (fullerene) molecules. Interestingly, the conformation of C aggregates was altered depending on the mixed solvents and their volume fraction in the organic phase, which strongly affected the structural properties of the PC60-C colloids. The particle facilitated strong interactions with a p-type core sphere when it was introduced as the shell part of a p-n heterojunction particle. This direct interaction provided effective electronic communication between p- and n-type particles, resulting in ultraefficient photonic properties, particularly in charge separation in aqueous heterostructured colloids. This enabled the development of an extremely efficient photovoltaic device with a 6.74% efficiency, which could provide the basis for creating high-performance water-processable solar cells based on p-n heterostructured NPs.
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http://dx.doi.org/10.1021/acsami.9b14240DOI Listing
October 2019

Engineered Tissue Development in Biofabricated 3D Geometrical Confinement-A Review.

ACS Biomater Sci Eng 2019 Aug 14;5(8):3688-3702. Epub 2019 Mar 14.

Department of Biomedical Engineering, State University of New York at Buffalo, Buffalo, New York 14260, United States.

Living tissue is a complex, heterogeneous structure where spatially organized ECMs present embedded cells with a variety of biochemical and mechanical signals. These signals are important to the formation of tissue structures and maintaining tissue homeostasis and physiological functions. Recent advances in biofabrication technologies have allowed the creation of 3D geometrical patterns that can guide the dynamic interaction between cells and ECM, leading to the formation of morphologically controlled engineered tissues that recapitulate the structure and function of native tissues. In this work, we first review advanced biofabrication technologies including lithography-based microfabrication and bioprinting that have been adopted to create a variety of geometrical confinements such as microgrooves and microribs, microwells, micropillar arrays, and microfibers. For each confinement type, we review geometrically guided formation and maturation of a variety of tissue types, including skeletal and cardiac muscles, epithelial tissue, endothelial tissue, and fibrous tissue. Geometrical confinements are important microenvironmental cues that can be utilized to promote the formation of biomimetic structures in engineered tissues.
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http://dx.doi.org/10.1021/acsbiomaterials.8b01195DOI Listing
August 2019

Increased mitochondrial fission of glomerular podocytes in diabetic nephropathy.

Endocr Connect 2019 Aug;8(8):1206-1212

Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China.

Aims: Previous studies showed that abnormal mitochondrial structure and function were involved in the pathological process of diabetic nephropathy (DN). The dynamic mitochondrial processes, including fusion and fission, maintain the mass and quantity of mitochondria. Podocyte injury is a critical factor in the development and progression of DN. The present study evaluated the mitochondrial fission of podocytes in patients with DN.

Methods: We recruited 31 patients with biopsy-confirmed DN. A quantitative analysis of the mitochondrial morphology was conducted with electron microscopy using a computer-assisted morphometric analysis application to calculate the aspect ratio values. Immunofluorescence assays were used to evaluate protein colocalization in the glomeruli of patients.

Results: The urine protein level was significantly increased in DN patients compared to non-DN patients (P < 0.001), and the mitochondria in the podocytes from DN patients were more fragmentated than those from patients without DN. The mitochondrial aspect ratio values were negatively correlated with the proteinuria levels (r = -0.574, P = 0.01), and multiple regression analysis verified that the mitochondrial aspect ratio was significantly and independently associated with the urine protein level (β = -0.519, P = 0.007). In addition, Drp1, a mitochondrial fission factor, preferentially combines with AKAP1, which is located in the mitochondrial membrane.

Conclusions: In the podocytes of DN patients, mitochondrial fragmentation was increased, and mitochondrial aspect ratio values were correlated with the proteinuria levels. The AKAP1-Drp1 pathway may contribute to mitochondrial fission in the pathogenesis of DN.
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http://dx.doi.org/10.1530/EC-19-0234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709540PMC
August 2019

A Nonsense Mutation in COL4A4 Gene Causing Isolated Hematuria in Either Heterozygous or Homozygous State.

Front Genet 2019 2;10:628. Epub 2019 Jul 2.

Renal Department, Renmin Hospital of Wuhan University, Wuhan, China.

Alport syndrome (AS) is a hereditary nephropathy characterized by glomerular basement membrane lesions. AS shows a relatively rare entity with autosomal dominant gene mutation (accounts for less than 5% of AS cases) and is widely believed to be a consequence of heterozygous variants in the and genes. Until now, there have been no reports of homozygous variants in genes in AS patients, and it is scarce to detect both homozygous and heterozygous variants in a single AS pedigree. We performed genetic analysis by exome sequencing (exome-seq) in a Chinese family with AS and found four individuals harboring the c.4599T > G variant, a novel nonsense mutation that gains stop codon and results in a truncated protein. The proband and her two siblings were determined to be heterozygous, whereas their mother was homozygous. The proband satisfied the criteria for the diagnosis of AS, which included clinical manifestations of microscopic hematuria and proteinuria, and pathological features of the glomerular basement membrane (GBM), including irregular thickening and splitting. However, the other three individuals who were homozygous or heterozygous for the variant exhibited mild clinical features with isolated microscopic hematuria. In summary, we identified a novel pathogenic variant in either the heterozygous or homozygous state of the gene in a Chinese family with AS. Our results also suggest that the severity of clinical manifestations may not be entirely attributed to by the genetic variant itself in patients.
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http://dx.doi.org/10.3389/fgene.2019.00628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614519PMC
July 2019

Charge-switchable polymeric complex for glucose-responsive insulin delivery in mice and pigs.

Sci Adv 2019 07 10;5(7):eaaw4357. Epub 2019 Jul 10.

Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.

Glucose-responsive insulin delivery systems with robust responsiveness that has been validated in animal models, especially in large animal models, remain elusive. Here, we exploit a new strategy to form a micro-sized complex between a charge-switchable polymer with a glucose-sensing moiety and insulin driven by electrostatic interaction. Both high insulin loading efficiency (95%) and loading capacity (49%) can be achieved. In the presence of a hyperglycemic state, the glucose-responsive phenylboronic acid (PBA) binds glucose instantly and converts the charge of the polymeric moiety from positive to negative, thereby enabling the release of insulin from the complex. Adjusting the ratio of the positively charged group to PBA achieves inhibited insulin release from the complex under normoglycemic conditions and promoted release under hyperglycemic conditions. Through chemically induced type 1 diabetic mouse and swine models, in vivo hyperglycemia-triggered insulin release with fast response is demonstrated after the complex is administrated by either subcutaneous injection or transdermal microneedle array patch.
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http://dx.doi.org/10.1126/sciadv.aaw4357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620100PMC
July 2019

Semi-artificial Photosynthetic CO Reduction through Purple Membrane Re-engineering with Semiconductor.

J Am Chem Soc 2019 07 17;141(30):11811-11815. Epub 2019 Jul 17.

Center for Nanoscale Materials , Argonne National Laboratory , Argonne , Illinois 60439 , United States.

The engineering of biological pathways with man-made materials provides inspiring blueprints for sustainable fuel production. Here, we leverage a top-down cellular engineering strategy to develop a new semi-artificial photosynthetic paradigm for carbon dioxide reduction via enveloping purple membrane-derived vesicles over Pd-deposited hollow porous TiO nanoparticles. In this biohybrid, the membrane protein, bacteriorhodopsin, not only retains its native biological function of pumping protons but also acts as a photosensitizer that injects light-excited electrons into the conduction band of TiO. As such, the electrons trapped on Pd cocatalysts and the protons accumulated inside the cytomimetic architecture act in concert to reduce CO via proton-coupled multielectron transfer processes. This study provides an alternative toolkit for developing robust semi-artificial photosynthetic systems for solar energy conversion.
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http://dx.doi.org/10.1021/jacs.9b05564DOI Listing
July 2019

Small GTPase Arf6 regulates diabetes-induced cholesterol accumulation in podocytes.

J Cell Physiol 2019 12 17;234(12):23559-23570. Epub 2019 Jun 17.

Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.

Podocyte injury is a critical factor for the initiation and progression of diabetic kidney disease (DKD). However, the underlying mechanisms of podocyte injury in DKD have not been completely elucidated. Studies suggested that intracellular cholesterol accumulation was correlated with podocyte injury, but the cause of podocyte cholesterol disorders in DKD are still unknown. ADP-ribosylation factor 6 (Arf6) is a small GTPase with pleiotropic effects and has previously been shown to regulate ATP-binding cassette transporter 1 (ABCA1) recycling, and thus, cholesterol homeostasis. However, Arf6 involvement in cholesterol metabolism in podocytes is scarce. To investigate the role of Arf6 in cholesterol modulation in podocytes, the effect of Arf6 on the regulation of the cholesterol transporter ABCA1 was studied in podocytes in vivo and in vitro. Intracellular cholesterol accumulation was significantly increased in podocytes from streptozotocin-induced diabetic rats and that hyperglycemia downregulated the expression of Arf6. Arf6 knockdown could cause ABCA1 recycling disorders, and thus, further aggravate cholesterol accumulation in podocytes under high-glucose (HG) conditions. Our results demonstrate that HG-induced cholesterol accumulation and cellular injury in podocytes may be related to the recycling disorder of ABCA1 caused by the downexpression of Arf6 in DKD.
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http://dx.doi.org/10.1002/jcp.28924DOI Listing
December 2019

Microclot array elastometry for integrated measurement of thrombus formation and clot biomechanics under fluid shear.

Nat Commun 2019 05 3;10(1):2051. Epub 2019 May 3.

Department of Biomedical Engineering, State University of New York at Buffalo, Buffalo, NY, 14260, USA.

Blood clotting at the vascular injury site is a complex process that involves platelet adhesion and clot stiffening/contraction in the milieu of fluid flow. An integrated understanding of the hemodynamics and tissue mechanics regulating this process is currently lacking due to the absence of an experimental system that can simultaneously model clot formation and measure clot mechanics under shear flow. Here we develop a microfluidic-integrated microclot-array-elastometry system (clotMAT) that recapitulates dynamic changes in clot mechanics under physiological shear. Treatments with procoagulants and platelet antagonists and studies with diseased patient plasma demonstrate the ability of the system to assay clot biomechanics associated with common antiplatelet treatments and bleeding disorders. The changes of clot mechanics under biochemical treatments and shear flow demonstrate independent yet equally strong effects of these two stimulants on clot stiffening. This microtissue force sensing system may have future research and diagnostic potential for various bleeding disorders.
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http://dx.doi.org/10.1038/s41467-019-10067-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499828PMC
May 2019

Bioinspired and Biomimetic Nanomedicines.

Acc Chem Res 2019 05 12;52(5):1255-1264. Epub 2019 Apr 12.

Department of Bioengineering , University of California , Los Angeles , California 90095 , United States.

Nanomedicine development aims to enhance the efficacy, accuracy, safety, and/or compliance of diagnosis and treatment of diseases by leveraging the unique properties of engineered nanomaterials. To this end, a multitude of organic and inorganic nanoparticles have been designed to facilitate drug delivery, sensing, and imaging, some of which are currently in clinical trials or have been approved by the Food and Drug Administration (FDA). In the process, the increasing knowledge in understanding how natural particulates, including cells, pathogens, and organelles, interact with body and cellular systems has spurred efforts to mimic their morphology and functions for developing new generations of nanomedicine formulations. In addition, the advances in bioengineering tools, bioconjugation chemistries, and bio-nanotechnologies have further enabled researchers to exploit these natural particulates for theranostic purposes. In this Account, we will discuss the recent progress in our lab on engineering bioinspired and biomimetic synthetic and cellular systems toward rational design of nanomedicine platforms for treating diabetes and cancer. Inspired by the structure and response mechanism of pancreatic β-cells, we synthesized a series of insulin granule-like vesicles that can respond to high blood or intestinal glucose levels for aiding in transdermal or oral insulin delivery, respectively. Then, to more closely mimic the multicompartmental architecture of β-cells, we further developed synthetic artificial cells with vesicle-in-vesicle superstructures which can sense blood glucose levels and dynamically release insulin via a membrane fusion process. Meanwhile, clues drawn from the traits of anaerobic bacteria that selectively invade and proliferate in solid tumors inspired the synthesis of a light-tuned hypoxia-responsive nanovesicle for implementing synergistic cancer therapy. In parallel, we also studied how autologous particulates could be recruited for developing advanced drug delivery systems. Through combination of genetic engineering and top-down cell engineering technologies, biomimetic nanomedicines derived from cytoplasmic membrane with programmed death 1 (PD-1) receptors expressed on surfaces were generated and employed for cancer immunotherapy. Based on our earlier study where aPD-L1 (antibodies against PD ligand 1)-conjugated platelets could release aPD-L1-bearing particles in situ and inhibit postsurgical tumor recurrence, we further genetically engineered megakaryocytes, the precursor cells of platelets, to express PD-1 receptors. In this way, platelets born with checkpoint blocking activity could be produced directly in vitro, avoiding post chemical modification processes while exerting similar therapeutic impact. As a further extension, by virtue of the bone marrow-homing ability of hematopoietic stem cells (HSCs), we recently conceived a cell-combination strategy by conjugating HSCs with platelets decorated with antibodies against PD1 (aPD-1) to suppress the growth and recurrence of leukemia. While we are still on the way of digging deep to understand and optimize bioinspired and biomimetic drug carriers, we expect that the strategies summarized in this Account would contribute to the development of advanced nanomedicines.
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http://dx.doi.org/10.1021/acs.accounts.9b00079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293770PMC
May 2019