Publications by authors named "Deling Kong"

323 Publications

Nitrate-functionalized patch confers cardioprotection and improves heart repair after myocardial infarction via local nitric oxide delivery.

Nat Commun 2021 07 23;12(1):4501. Epub 2021 Jul 23.

State key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials (Ministry of Education), College of Life Sciences, Nankai University, Tianjin, China.

Nitric oxide (NO) is a short-lived signaling molecule that plays a pivotal role in cardiovascular system. Organic nitrates represent a class of NO-donating drugs for treating coronary artery diseases, acting through the vasodilation of systemic vasculature that often leads to adverse effects. Herein, we design a nitrate-functionalized patch, wherein the nitrate pharmacological functional groups are covalently bound to biodegradable polymers, thus transforming small-molecule drugs into therapeutic biomaterials. When implanted onto the myocardium, the patch releases NO locally through a stepwise biotransformation, and NO generation is remarkably enhanced in infarcted myocardium because of the ischemic microenvironment, which gives rise to mitochondrial-targeted cardioprotection as well as enhanced cardiac repair. The therapeutic efficacy is further confirmed in a clinically relevant porcine model of myocardial infarction. All these results support the translational potential of this functional patch for treating ischemic heart disease by therapeutic mechanisms different from conventional organic nitrate drugs.
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http://dx.doi.org/10.1038/s41467-021-24804-3DOI Listing
July 2021

PolyTLR7/8a-conjugated, antigen-trapping gold nanorods elicit anticancer immunity against abscopal tumors by photothermal therapy-induced in situ vaccination.

Biomaterials 2021 Jun 8;275:120921. Epub 2021 Jun 8.

Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China. Electronic address:

Nanovaccine can elicit antigen-specific immune responses against tumor cells expressing homologous antigens and has attracted enormous attention in cancer immunotherapy. However, tumor heterogeneity remarkably hinders the development of nanovaccines. Here we demonstrate that PTT-induced in situ vaccination cancer therapy can elicit potent antitumor immunity against disseminated and metastatic tumors. Gold nanorods (AuNRs) covalently coupled with amphiphilic polyTLR7/8a and MMP-2-sensitive R9-PEG conjugate (AuNRs-IMQD-R9-PEG) were developed as a new biocompatible PTT agent with favorable photothermal efficiency and stability. Importantly, AuNRs-IMQD-R9-PEG can effectively absorb tumor-derived protein antigens, forming nanovaccines directly in vivo and enhance the activation of host dendritic cells (DCs), thereby amplifying adaptive antitumor T-cell responses, triggering effector memory immune responses, and activating innate antitumor immunity. Remarkably, peri-tumoral administration of low-dose multifunctional AuNRs followed by non-invasive near-infrared (NIR) laser irradiation enables efficient tandem PTT-vaccination treatment modality that can inhibit local as well as untreated distant and metastatic tumors in mice inoculated with poorly immunogenic, highly metastatic 4T1 tumors. Our findings indicate that AuNRs-IMQD-R9-PEG-mediated in situ cancer vaccination provides a powerful immunotherapy characterized by markedly increased infiltration of effector CD8 T, natural killer T (NKT) cells in tumors and long-term animal survival, thus, offering a promising therapeutic strategy for advanced, disseminated cancers.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120921DOI Listing
June 2021

Supramolecular co-assembly of self-adjuvanting nanofibrious peptide hydrogel enhances cancer vaccination by activating MyD88-dependent NF-κB signaling pathway without inflammation.

Bioact Mater 2021 Nov 16;6(11):3924-3934. Epub 2021 Apr 16.

Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China.

Peptide vaccine targeting tumor-specific antigens is a promising cancer treatment regimen. However, peptide vaccines are commonly low-immunogenic, leading to suboptimal antitumor T-cell responses. Current peptide vaccination approaches are challenged by the variability of peptide physicochemical characters and vaccine formulations, flexibility, and the broad feasibility. Here, the supramolecular co-assembly of antigen epitope-conjugated peptides (ECPs) targeting CD8 or CD4 T-cell receptors was used to engineer a nanofibrious hydrogel vaccine platform. This approach provided precise and tunable loading of peptide antigens in nanofibers, which notably increased the antigen uptake, cross-presentation, and activation of dendritic cells (DCs). Immunization in mice indicated that the co-assembled peptide hydrogel did not induce local inflammation responses and elicited significantly promoted T-cell immunity by activating the MyD88-dependent NF-κB signaling pathway in DCs. Vaccination of mice using co-assembled peptide vaccine stimulated both enhanced CD8 and CD4 T cells against EG.7-OVA tumors without additional immunoadjuvants or delivery systems, and resulted in a more remarkable cancer immunotherapy efficacy, compared with free peptide vaccine or aluminum-adjuvanted peptide formulation. Altogether, peptide co-assembly demonstrated by three independent pairs of ECPs is a facile, customizable, and chemically defined approach for co-delivering peptide antigens in self-adjuvanting hydrogel vaccines that could induce stronger anticancer T-cell responses.
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http://dx.doi.org/10.1016/j.bioactmat.2021.03.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080410PMC
November 2021

Nanozyme-Powered Giant Unilamellar Vesicles for Mimicry and Modulation of Intracellular Oxidative Stress.

ACS Appl Mater Interfaces 2021 May 28;13(18):21087-21096. Epub 2021 Apr 28.

Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China.

The bottom-up construction of enzyme-based artificial cells is generating increasing interest, but achieving artificial cells for "all artificial modules" remains challenging in synthetic biology. Here, we introduce a fully synthetic cell system by integration of biomimetic nanozymes into giant unilamellar vesicles (GUVs). To mimic native peroxidase for free radical generation by taking advantage of Fenton catalysis reactions, we designed and prepared a de novo artificial nanozyme composed of ferritin heavy-chain scaffold protein and catalytic FeO nanoparticles as the active center. As two examples in bioapplications, we showed this nanozyme-powered GUV system not only mimics intracellular oxidative stress pathways but also induces tumor cell death by sensing and responding to external chemical signals. Specifically, we recreated intracellular biochemical events, including DNA damage and lipid peroxidation, in the compartmentalized GUVs by taking advantage of nanozyme induction of defined catalytic reactions. Additionally, the GUV system also actively induced DNA double-strand breakage and lipid damage of tumor cells, in response to the high expression of HO within the tumor microenvironment. This concept-of-proof study offers a promising option for defining catalysis in biological systems and gives new insights into the de novo creation of artificial cells in a fully synthetic manner.
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http://dx.doi.org/10.1021/acsami.1c05512DOI Listing
May 2021

Enhanced Antitumor Immune Responses via a Self-Assembled Carrier-Free Nanovaccine.

Nano Lett 2021 05 22;21(9):3965-3973. Epub 2021 Apr 22.

The Tianjin Key Laboratory of Biomaterials, Institute of Biomedical Engineering, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin 300192, China.

Nanovaccines have emerged as promising agents for cancer immunotherapy. However, insufficient antitumor immunity caused by inefficient antigen/adjuvant loading and complicated preparation processes are the major obstacles that limit their clinical application. Herein, two adjuvants, monophosphatidyl A (MPLA) and CpG ODN, with antigens were designed into a nanovaccine to overcome the above obstacles. This nanovaccine was constructed with adjuvants (without additional materials) through facile self-assembly, which not only ensured a high loading efficacy and desirable safety but also facilitated clinical translation for convenient fabrication. More importantly, the selected adjuvants could achieve a notable immune response through synergistic activation of Toll-like receptor 4 (TLR4) and TLR9 signaling pathways, and the resulting nanovaccine remarkably inhibited the tumor growth and prolonged the survival of tumor-implanted mice. This nanovaccine system provides an effective strategy to construct vaccines for cancer immunotherapy.
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http://dx.doi.org/10.1021/acs.nanolett.1c00648DOI Listing
May 2021

Highly interconnected inverse opal extracellular matrix scaffolds enhance stem cell therapy in limb ischemia.

Acta Biomater 2021 Jul 18;128:209-221. Epub 2021 Apr 18.

College of Life Sciences, Key Laboratory of Bioactive Materials (Ministry of Education), State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China. Electronic address:

The therapeutic effectiveness of cell transplantation in treatment of diseases and injuries is often limited by low cell retention, survivability, and engraftment. Extracellular matrix (ECM)-derived scaffolds are capable of controlling cell responses, thereby offering potential solutions to current challenges associated with cell therapy. However, it remains a technical challenge to produce ECM scaffolds with highly interconnected porous structure specifically required for cell transplantation. Here, we developed inverse opal porous extracellular matrix (ioECM) scaffolds through subcutaneous implantation of sacrificial templates assembled from polymer microspheres, followed by removal of the microsphere template and cellular content. Such highly interconnected porous ioECM scaffolds supported the anchorage, survival, viability, anti-apoptotic and paracrine activities of rat bone marrow mesenchymal stem cells (BMSCs), which further promoted endothelial cell migration and tube formation and viability. Upon transplantation into nude mouse critical limb ischemic model, ioECM promoted the engraftment of laden BMSCs, facilitated interconnected vascular network formation with accelerated recovery of blood perfusion and inhibited muscle atrophy and fibrosis. Our study demonstrates a unique strategy to engineer highly porous yet well-interconnected ECM scaffolds specifically for cell transplantation with marked improvement of survivability and vascularization, which offers an essential step toward the success of cell therapy and regenerative medicine. STATEMENT OF SIGNIFICANCE: Cell-based therapy has a good developing foreground applied in a variety of tissue regeneration. Extracellular matrix (ECM) scaffolds is an optimal choice for cell delivery duo to its superior biocompatibility and favorable immune responses. However, the current ECM scaffolds lacking of the controllable pore structure restrict the cell delivery efficiency and therapeutic outcome. Here, we fabricated highly interconnected inverse opal extracellular matrix (ioECM) scaffolds, which can enhance the effect of stem cell therapy in limb ischemic model by improving the survival, viability, and paracrine activities of stem cells. Our study provides reference value for the design and fabrication of ECM based biomaterials for cell transplantation.
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http://dx.doi.org/10.1016/j.actbio.2021.04.025DOI Listing
July 2021

Aligned microfiber-induced macrophage polarization to guide schwann-cell-enabled peripheral nerve regeneration.

Biomaterials 2021 05 27;272:120767. Epub 2021 Mar 27.

College of Life Sciences, Key Laboratory of Bioactive Materials (Ministry of Education), State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China. Electronic address:

Mechanistic understanding of the topological cues delivered by biomaterials in promotion of oriented tissue regeneration (e.g., peripheral nerve regrowth) remains largely elusive. Here, we engineered nerve conduits composed of oriented microfiber-bundle cores and randomly organized nanofiber sheaths to particularly interrogate the regulatory mechanism of microfiber orientation on promoted peripheral nerve regeneration. With comprehensive yet systematic analyses, we were able to elucidate the intricate cascade of biological responses associated with conduit-assisted nerve regrowth, i.e., oriented microfibers facilitated macrophage recruitment and subsequent polarization toward a pro-healing phenotype, which in turn promoted Schwann cell (SC) migration, myelinization and axonal extension. Pronounced improvement of nerve regeneration in rat sciatic nerve injury was evidenced with enhanced electrophysiologic function, sciatic functional index and alleviated muscle atrophy 3 months post-implantation. The obtained results offer essential insights on the topological regulation of biomaterials in functional nerve tissue regeneration via immune modulation.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120767DOI Listing
May 2021

Cascaded amplification of intracellular oxidative stress and reversion of multidrug resistance by nitric oxide prodrug based-supramolecular hydrogel for synergistic cancer chemotherapy.

Bioact Mater 2021 Oct 13;6(10):3300-3313. Epub 2021 Mar 13.

Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China.

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http://dx.doi.org/10.1016/j.bioactmat.2021.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970318PMC
October 2021

In Vivo Insulin Peptide Autoantigen Delivery by Mannosylated Sodium Alginate Nanoparticles Delayed but Could Not Prevent the Onset of Type 1 Diabetes in Nonobese Diabetic Mice.

Mol Pharm 2021 04 18;18(4):1806-1818. Epub 2021 Mar 18.

Tianjin Key Laboratory of Biomedical Materials, Biomedical Barriers Research Center, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China.

Type 1 diabetes (T1D) is an autoimmune subtype of diabetes, mainly caused by the immune attack of self-insulin-producing cells. Immune modulation that delays the onset of T1D is able to reduce diabetic complications and mortality. We have previously reported that mannosylated sodium alginate nanoparticles (MAN-ALG) exhibited excellent dendritic cell targeting and in vivo antigen delivery efficacy. To investigate the role of MAN-ALG in an autoimmune context, we loaded the MAN-ALG with Ins2, a T1D autoantigen [MAN-ALG(PEP)], for T1D immune tolerance induction in nonobese diabetic (NOD) mice. We observed the delayed onset of T1D occurrence and some degree of blood glucose reduction accompanied by a larger islet area, attributable to augmented T-regulatory cell proportion in mice treated with MAN-ALG(PEP). However, MAN-ALG was also found to elicit lysosomal escape and cross-presentation of Ins2 in bone marrow-derived dendritic cells, leading to the immune activation of Ins2-recognizing T cells and destruction of Ins2-expressing islet cells. This dual impact resulted in delayed but a nonpreventive effect of MAN-ALG(PEP) on the T1D onset in NOD mice. Considering the potent immune stimulatory property of MAN-ALG, cautions should be implemented when using alginate-based biomaterials in an autoimmune context. Moreover, it is also noted that regarding the in vivo outcome of immune therapies, biomaterial-based delivery systems and their detailed role on immune regulation need to be examined.
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http://dx.doi.org/10.1021/acs.molpharmaceut.1c00054DOI Listing
April 2021

The effect of hypoxia-mimicking responses on improving the regeneration of artificial vascular grafts.

Biomaterials 2021 04 3;271:120746. Epub 2021 Mar 3.

Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin, 300071, China. Electronic address:

Cellular transition to hypoxia following tissue injury, has been shown to improve angiogenesis and regeneration in multiple tissues. To take advantage of this, many hypoxia-mimicking scaffolds have been prepared, yet the oxygen access state of implanted artificial small-diameter vascular grafts (SDVGs) has not been investigated. Therefore, the oxygen access state of electrospun PCL grafts implanted into rat abdominal arteries was assessed. The regions proximal to the lumen and abluminal surfaces of the graft walls were normoxic and only the interior of the graft walls was hypoxic. In light of this differential oxygen access state of the implanted grafts and the critical role of vascular regeneration on SDVG implantation success, we investigated whether modification of SDVGs with HIF-1α stabilizer dimethyloxalylglycine (DMOG) could achieve hypoxia-mimicking responses resulting in improving vascular regeneration throughout the entirety of the graft wall. Therefore, DMOG-loaded PCL grafts were fabricated by electrospinning, to support the sustained release of DMOG over two weeks. In vitro experiments indicated that DMOG-loaded PCL mats had significant biological advantages, including: promotion of human umbilical vein endothelial cells (HUVECs) proliferation, migration and production of pro-angiogenic factors; and the stimulation of M2 macrophage polarization, which in-turn promoted macrophage regulation of HUVECs migration and smooth muscle cells (SMCs) contractile phenotype. These beneficial effects were downstream of HIF-1α stabilization in HUVECs and macrophages in normoxic conditions. Our results indicated that DMOG-loaded PCL grafts improved endothelialization, contractile SMCs regeneration, vascularization and modulated the inflammatory reaction of grafts in abdominal artery replacement models, thus promoting vascular regeneration.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120746DOI Listing
April 2021

A Bacteria-Inspired Morphology Genetic Biomedical Material: Self-Propelled Artificial Microbots for Metastatic Triple Negative Breast Cancer Treatment.

ACS Nano 2021 03 24;15(3):4845-4860. Epub 2021 Feb 24.

Huaxi MR Research Center (HMRRC) Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital Sichuan University, Chengdu 610041, P. R. China.

Morphology genetic biomedical materials (MGBMs), referring to fabricating materials by learning from the genetic morphologies and strategies of natural species, hold great potential for biomedical applications. Inspired by the cargo-carrying-bacterial therapy (microbots) for cancer treatment, a MGBM (artificial microbots, AMBs) was constructed. Rather than the inherent bacterial properties (cancerous chemotaxis, tumor invasion, cytotoxicity), AMBs also possessed ingenious nitric oxide (NO) generation strategy. Mimicking the bacterial construction, the hyaluronic acid (HA) polysaccharide was induced as a coating capsule of AMBs to achieve long circulation in blood and specific tissue preference (tumor tropism). Covered under the capsule-like polysaccharide was the combinatorial agent, the self-assembly constructed by the amphiphilic dendrons with abundant l-arginine residues peripherally (as endogenous NO donor) and hydrophobic chemotherapeutic drugs at the core stacking on the surface of SWNTs (the photothermal agent) for a robust chemo-photothermal therapy (chemo-PTT) and the elicited immune therapy. Subsequently, the classic inducible nitric oxide synthase (iNOS) pathway aroused by immune response was revolutionarily utilized to oxidize the l-arginine substrates for NO production, the process for which could also be promoted by the high reactive oxygen species level generated by chemo-PTT. The NO generated by AMBs was intended to regulate vasodilation and cause a dramatic invasion (as the microbots) to disperse the therapeutic agents throughout the solid tumor for a much more enhanced curative effect, which we defined as "self-propulsion". The self-propelled AMBs exhibiting impressive primary tumor ablation, as well as the distant metastasis regression to conquer the metastatic triple negative breast cancer, provided pioneering potential therapeutic opportunities, and enlightened broad prospects in biomedical application.
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http://dx.doi.org/10.1021/acsnano.0c09594DOI Listing
March 2021

Biofabrication of poly(l-lactide-co-ε-caprolactone)/silk fibroin scaffold for the application as superb anti-calcification tissue engineered prosthetic valve.

Mater Sci Eng C Mater Biol Appl 2021 Feb 8;121:111872. Epub 2021 Jan 8.

Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China. Electronic address:

In this study, electrospun scaffolds were fabricated by blending poly(l-lactide-co-ε-caprolactone) (PLCL) and silk fibroin (SF) with different ratios, and further the feasibility of electrospun PLCL/SF scaffolds were evaluated for application of tissue engineered heart valve (TEHV). Scanning electron microscopy (SEM) results showed that the surface of PLCL/SF electrospun scaffolds was smooth and uniform while the mechanical properties were appropriate as valve prosthesis. In vitro cytocompatibility evaluation results demonstrated that all of the PLCL/SF electrospun scaffolds were cytocompatible and valvular interstitial cells (VICs) cultured on PLCL/SF scaffolds of 80/20 & 70/30 ratios exhibited the best cytocompatibility. The in vitro osteogenic differentiation of VICs including alkaline phosphatase (ALP) activity and quantitative polymerase chain reaction (qPCR) assays indicated that PLCL/SF scaffolds of 80/20 & 90/10 ratios behaved better anti-calcification ability. In the in vivo calcification evaluation model of rat subdermal implantation, PLCL/SF scaffolds of 80/20 & 90/10 ratios presented better anti-calcification ability, which was consistent with the in vitro results. Moreover, PLCL/SF scaffolds of 80/20 & 70/30 ratios showed significantly enhanced cell infiltration and M2 macrophage with higher CD206+/CD68+ ratio. Collectively, our data demonstrated that electrospun scaffolds with the PLCL/SF ratio of 80/20 hold great potential as TEHV materials.
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http://dx.doi.org/10.1016/j.msec.2021.111872DOI Listing
February 2021

Design and Evaluation of a Polypeptide that Mimics the Integrin Binding Site for EDA Fibronectin to Block Profibrotic Cell Activity.

Int J Mol Sci 2021 Feb 4;22(4). Epub 2021 Feb 4.

Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China.

Fibrosis is characterized by excessive production of disorganized collagen- and fibronectin-rich extracellular matrices (ECMs) and is driven by the persistence of myofibroblasts within tissues. A key protein contributing to myofibroblast differentiation is extra domain A fibronectin (EDA-FN). We sought to target and interfere with interactions between EDA-FN and its integrin receptors to effectively inhibit profibrotic activity and myofibroblast formation. Molecular docking was used to assist in the design of a blocking polypeptide (antifibrotic 38-amino-acid polypeptide, AF38Pep) for specific inhibition of EDA-FN associations with the fibroblast-expressed integrins αβ and αβ. Blocking peptides were designed and evaluated in silico before synthesis, confirmation of binding specificity, and evaluation in vitro. We identified the high-affinity EDA-FN C-C' loop binding cleft within integrins αβ and αβ. The polypeptide with the highest predicted binding affinity, AF38Pep, was synthesized and could achieve specific binding to myofibroblast fibronectin-rich ECM and EDA-FN C-C' loop peptides. AF38Pep demonstrated potent myofibroblast inhibitory activity at 10 µg/mL and was not cytotoxic. Treatment with AF38Pep prevented integrin αβ-mediated focal adhesion kinase (FAK) activation and early signaling through extracellular-signal-regulated kinases 1 and 2 (ERK1/2), attenuated the expression of pro-matrix metalloproteinase 9 (MMP9) and pro-MMP2, and inhibited collagen synthesis and deposition. Immunocytochemistry staining revealed an inhibition of α-smooth muscle actin (α-SMA) incorporation into actin stress fibers and attenuated cell contraction. Increases in the expression of mRNA associated with fibrosis and downstream from integrin signaling were inhibited by treatment with AF38Pep. Our study suggested that AF38Pep could successfully interfere with EDA-FN C-C' loop-specific integrin interactions and could act as an effective inhibitor of fibroblast of myofibroblast differentiation.
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http://dx.doi.org/10.3390/ijms22041575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913925PMC
February 2021

Biomimetic Design of Mitochondria-Targeted Hybrid Nanozymes as Superoxide Scavengers.

Adv Mater 2021 Mar 22;33(9):e2006570. Epub 2021 Jan 22.

Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China.

Development of enzyme mimics for the scavenging of excessive mitochondrial superoxide (O ) can serve as an effective strategy in the treatment of many diseases. Here, protein reconstruction technology and nanotechnology is taken advantage of to biomimetically create an artificial hybrid nanozyme. These nanozymes consist of ferritin-heavy-chain-based protein as the enzyme scaffold and a metal nanoparticle core as the enzyme active center. This artificial cascade nanozyme possesses superoxide dismutase- and catalase-like activities and also targets mitochondria by overcoming multiple biological barriers. Using cardiac ischemia-reperfusion animal models, the protective advantages of the hybrid nanozymes are demonstrated in vivo during mitochondrial oxidative injury and in the recovery of heart functionality following infarction via systemic delivery and localized release from adhesive hydrogels (i.e., cardiac patch), respectively. This study illustrates a de novo design strategy in the development of enzyme mimics and provides a promising therapeutic option for alleviating oxidative damage in regenerative medicine.
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http://dx.doi.org/10.1002/adma.202006570DOI Listing
March 2021

ICG/l-Arginine Encapsulated PLGA Nanoparticle-Thermosensitive Hydrogel Hybrid Delivery System for Cascade Cancer Photodynamic-NO Therapy with Promoted Collagen Depletion in Tumor Tissues.

Mol Pharm 2021 03 11;18(3):928-939. Epub 2021 Jan 11.

Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.

Photodynamic therapy (PDT) is promising for clinical cancer therapy; however, the efficacy was limited as an individual treatment regimen. Here, an approach synergistically combining PDT and nitric oxide (NO) gas therapy along with destruction of the tumor extracellular matrix (ECM) was presented to eliminate cancer. Specifically, the NO donor l-arginine (l-Arg) and the photosensitizer indocyanine green (ICG) were co-encapsulated in poly(lactic-glycolic acid) (PLGA) nanoparticles and then loaded into the poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL) hydrogel to develop an injectable, thermosensitive dual drug delivery system ([email protected]@l-Arg/Gel). Significantly, reactive oxygen species (ROS) produced by [email protected]@l-Arg/Gel under near-infrared (NIR) light irradiation could not only result in the apoptosis of cancer cells but also oxidize l-Arg to generate NO, which could suppress the proliferation of cancer cells. Moreover, ROS could further oxidize NO to generate peroxynitrite anions (ONOO). ONOO could activate matrix metalloproteinases (MMPs), which notably degraded collagen in ECM so as to damage the tumor microenvironment. [email protected]@l-Arg/Gel significantly increased the antitumor efficacy against highly malignant 4T1 tumors in mice. Taken together, [email protected]@l-Arg/Gel is a multifunctional platform that provides a novel strategy for cancer treatment with cascade amplification of the ROS oxidation effect, which holds great potential in clinical translation.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00937DOI Listing
March 2021

Polymer-lipid hybrid nanovesicle-enabled combination of immunogenic chemotherapy and RNAi-mediated PD-L1 knockdown elicits antitumor immunity against melanoma.

Biomaterials 2021 01 26;268:120579. Epub 2020 Nov 26.

Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China. Electronic address:

Immunotherapy has revolutionized cancer treatment; however, only a limited portion of patients show responses to currently available immunotherapy regimens. Here, we demonstrate that RNA interference (RNAi) combined with immunogenic chemotherapy can elicit potent antitumor immunity against melanoma. Specially, we developed cationic polymer-lipid hybrid nanovesicles (P/LNVs) as a new delivery system for doxorubicin and small interfering RNA (siRNA) with extensive cytotoxicity and gene silencing efficiency towards B16 cells. The deployment of doxorubicin-loaded P/LNVs augmented the expression and presentation of endogenous tumor antigens directly in situ by inducing the immunogenic cell death of B16 cells through poly(ADP-ribose) polymerase 1-dependent (PARP1) apoptosis pathway; thereby, eliciting remarkable antitumor immune responses in mice. Leveraging dying B16 cells as a vaccination strategy in combination with RNAi-based programmed cell death ligand 1 (PD-L1) knockdown showed efficacy in both prophylactic and metastasis melanoma settings. Strikingly, PD-L1 blockade synergized with a sub-therapeutic dose of doxorubicin triggered robust therapeutic antitumor T-cell responses and eradicated pre-established tumors in 30% of mice bearing B16 melanoma. Our findings indicated that this combination treatment provided a new powerful immunotherapy modality, characterized by markedly increased infiltration of effector CD8 T cells and effective alleviation of the immunosuppressive microenvironment in tumors. P/LNVs is a versatile and highly scalable carrier that can enable a broad combination of nanomedicine and RNAi, providing new therapeutic strategies for advanced cancers.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120579DOI Listing
January 2021

Progress in research on effect of PM on occurrence and development of atherosclerosis.

J Appl Toxicol 2021 05 1;41(5):668-682. Epub 2020 Dec 1.

Tianjin Key Laboratory of Urban Transport Emission Research, State Environmental Protection Key Laboratory of Urban Ambient Air Particulate Matter Pollution Prevention and Control, College of Environmental Science and Engineering, Nankai University, Tianjin, China.

Fine particulate matter ≤2.5 μm (PM ) air pollution is regarded as one of the prominent risk factors that contributes to morbidity and mortality globally, among which cardiovascular disease (CVD) has been strongly associated with PM exposure and is a leading cause of death. Atherosclerosis (AS), the common pathological basis of many CVDs, is a progressive syndrome characterized by the accumulation of lipids and fibrous plaque in the arteries. Recent epidemiological and toxicological studies suggest that PM may also contribute to the development of AS, even at levels below the current air quality standards. In this paper, the complete pathological process of atherosclerotic plaque from occurrence to rupture leading to CVD was elaborated. Then, the growing epidemiological evidence linking PM to AS in humans was reviewed and summarized. Furthermore, the potential mechanisms of PM -mediated AS were discussed, including oxidative stress, inflammation, endothelial dysfunction, abnormal lipid metabolism, disturbance of the autonomic nervous system, and abnormal coagulation function. This paper aimed to provide a comprehensive view of the effect of PM on the occurrence and development of AS for better prevention and mitigation of adverse health impacts due to PM air pollution.
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http://dx.doi.org/10.1002/jat.4110DOI Listing
May 2021

A simple self-adjuvanting biomimetic nanovaccine self-assembled with the conjugate of phospholipids and nucleotides can induce a strong cancer immunotherapeutic effect.

Biomater Sci 2021 Jan;9(1):84-92

The Tianjin Key Laboratory of Biomaterials, Institute of Biomedical Engineering, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin 300192, China.

Biomimetic nanoparticles have potential applications in many fields due to their favorable properties. Here, we developed a self-adjuvanting biomimetic anti-tumor nanovaccine, which was self-assembled with an amphiphilic conjugate synthesized with the phospholipids of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and hydrophilic Toll-like receptor (TLR9) agonist CpG ODN. The nanovaccine could not only provide effective initial antigen stimulation and sustained long-term antigen supply with a controlled release, but also induce antigen cross-presentation via the MHC-I pathway initiating CD8+ T-cell responses. Moreover, the dense nucleotide shell around the nanovaccine could promote antigen endocytosis via various receptor-mediated pathways into dendritic cells. CpG ODN interacted with TLR9 triggering the cytokine secretion of TNF-α and IL-10, which further boosted the anti-tumor humoral and cellular immune responses, which led to a significant tumor suppressive effect and remarkable survival prolongation. So, this nanovaccine self-assembled with phospholipid-nucleotide amphiphiles can serve as a safe, simple and efficient approach for anti-tumor immunotherapy.
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http://dx.doi.org/10.1039/d0bm01333aDOI Listing
January 2021

Synthetic Polymeric Antibacterial Hydrogel for Methicillin-Resistant Infected Wound Healing: Nanoantimicrobial Self-Assembly, Drug- and Cytokine-Free Strategy.

ACS Nano 2020 10 25;14(10):12905-12917. Epub 2020 Sep 25.

Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.

Antibacterial hydrogels are attracting extensive attention in soft tissue repair and regeneration, including bacteria-infected-wound healing. The abuse of antibiotics leads to drug resistance. Recent developments have demonstrated that the delivery of inorganic bactericidal agents in hydrogels can drive the wound healing process; however, this approach is complicated by external light stimuli, cytotoxicity, nondegradability, and sophisticated fabrication. Herein, an inherent antibacterial, bioresorbable hydrogel was developed by the spontaneous self-aggregation of amphiphilic, oxadiazole-group-decorated quaternary ammonium salts (QAS)-conjugated poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCEC-QAS) micellar nanoantimicrobials for methicillin-resistant (MRSA)-infected cutaneous wound healing. The PCEC-QAS hydrogel showed a stable gel state within the temperature range of 5-50 °C and antibacterial efficacy against both Gram-negative and -positive bacteria and . Additionally, the PCEC-QAS hydrogel facilitated the cell spreading, proliferation, and migration without cytotoxicity. An degradation and skin defect healing study suggested the PCEC-QAS hydrogel was totally absorbed without local or systemic toxicity and could promote wound repair in the absence of drugs, cytokines, or cells. Significantly, this hydrogel accelerated the regeneration of a MRSA-infected full-thickness impaired skin wound by successfully reconstructing an intact and thick epidermis similar to normal mouse skin. Collectively, a self-assembling PCEC-QAS antibacterial hydrogel is a promising dressing material to promote skin regeneration and prevent bacterial infection without additional drugs, cells, light irradiation, or delivery systems, providing a simple but effective strategy for treating dermal wounds.
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http://dx.doi.org/10.1021/acsnano.0c03855DOI Listing
October 2020

Hybrid spherical nucleotide nanoparticles can enhance the synergistic anti-tumor effect of CTLA-4 and PD-1 blockades.

Biomater Sci 2020 Sep 28;8(17):4757-4766. Epub 2020 Jul 28.

The Tianjin Key Laboratory of Biomaterials, Institute of Biomedical Engineering, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin 300192, China.

Combined blockades of CTLA-4 and PD-1 can yield better overall complementary clinical outcomes than individual blockades, but the response rates are still relatively low. To investigate the anti-tumor effects of various combined strategies, we designed various spherical nucleotide nanoparticles (SNPs) loaded with CTLA-4 aptamer (cSNPs), PD-1 siRNA (pSNPs) or both (hybrid SNPs, or hSNPs). The results demonstrated that hSNPs could promote significantly stronger anti-tumor immune responses in a nonredundant fashion than the mixture of pSNPs and cSNPs (pSNPs & cSNPs). We reasoned that this is because all individual immune cells could receive both CTLA-4 and PD-1 blockades when they engulfed hSNPs, but it is much less likely that individual immune cells could receive both CTLA-4 and PD-1 blockades as many of them may not take both pSNPs and cSNPS from pSNPs & cSNPs. Further results revealed that the synergistic immune stimulatory effects of CTLA-4 and PD-1 blockades in the form of hSNPs were at least partly through regulating the immune suppressive function of both Tregs and TIM3 exhausted-like CD8 T cells and allowing effector T cells to expand. This mechanism is not identical to earlier reported mechanisms of CTLA-4 and PD-1 blockades.
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http://dx.doi.org/10.1039/d0bm00908cDOI Listing
September 2020

Supramolecular Nanofibers Containing Arginine-Glycine-Aspartate (RGD) Peptides Boost Therapeutic Efficacy of Extracellular Vesicles in Kidney Repair.

ACS Nano 2020 09 21;14(9):12133-12147. Epub 2020 Aug 21.

School of Medicine, Nankai University, Tianjin 300071, China.

Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSC-EVs) have been recognized as a promising cell-free therapy for acute kidney injury (AKI), which avoids safety concerns associated with direct cell engraftment. However, low stability and retention of MSC-EVs have limited their therapeutic efficacy. RGD (Arg-Gly-Asp) peptide binds strongly to integrins, which have been identified on the surface of MSC-EV membranes; yet RGD has not been applied to EV scaffolds to enhance and prolong bioavailability. Here, we developed RGD hydrogels, which we hypothesized could augment MSC-EV efficacy in the treatment of AKI models. tracking of the labeled EVs revealed that RGD hydrogels increased retention and stability of EVs. Integrin gene knockdown experiments confirmed that EV-hydrogel interaction was mediated by RGD-integrin binding. Upon intrarenal injection into mouse AKI models, EV-RGD hydrogels provided superior rescuing effects to renal function, attenuated histopathological damage, decreased tubular injury, and promoted cell proliferation in early phases of AKI. RGD hydrogels also augmented antifibrotic effects of MSC-EVs in chronic stages. Further analysis revealed that the presence of microRNA let-7a-5p in MSC-EVs served as the mechanism contributing to the reduced cell apoptosis and elevated cell autophagy in AKI. In conclusion, RGD hydrogels facilitated MSC-derived let-7a-5p-containing EVs, improving reparative potential against AKI. This study developed an RGD scaffold to increase the EV integrin-mediated loading and in turn improved therapeutic efficacy in renal repair; therefore this strategy shed light on MSC-EV application as a cell-free treatment for potentiated efficiency.
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http://dx.doi.org/10.1021/acsnano.0c05681DOI Listing
September 2020

Old Dog New Tricks: PLGA Microparticles as an Adjuvant for Insulin Peptide Fragment-Induced Immune Tolerance against Type 1 Diabetes.

Mol Pharm 2020 09 17;17(9):3513-3525. Epub 2020 Aug 17.

Tianjin Key Laboratory of Biomedical Materials, Biomedical Barriers Research Centre, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China.

Poly[lactic--(glycolic acid)] (PLGA) is arguably one of the most versatile synthetic copolymers used for biomedical applications. In vivo delivery of multiple substances including cells, pharmaceutical compounds, and antigens has been achieved by using PLGA-based micro-/nanoparticles although, presently, the exact biological impact of PLGA particles on the immune system remains controversial. Type 1 diabetes (T1D) is one subtype of diabetes characterized by the attack of immune cells against self-insulin-producing pancreatic islet cells. Considering the autoimmune etiology of T1D and the recent use of PLGA particles for eliciting desired immune responses in various aspects of immunotherapy, for the present study, a combination of Ins2 peptide (a known autoantigen of T1D) and PLGA microparticles was selected for T1D prevention assessment in nonobese diabetic (NOD) mice, a well-known animal model with spontaneous development of T1D. Thus, inoculation of PLGA microparticles + Ins2 completely prevented T1D development, significantly better than untreated controls and mice treated by either PLGA microparticles or Ins2 per se. Subsequent mechanistic investigation further revealed a facilitative role of PLGA microparticles in immune tolerance induction. In summary, our data demonstrate an adjuvant potential of PLGA microparticles in tolerance induction and immune remodulation for effective prevention of autoimmune diseases such as T1D.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00525DOI Listing
September 2020

Multifunctional Natural Polymer Nanoparticles as Antifibrotic Gene Carriers for CKD Therapy.

J Am Soc Nephrol 2020 10 7;31(10):2292-2311. Epub 2020 Aug 7.

Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China

Background: Progressive fibrosis is the underlying pathophysiological process of CKD, and targeted prevention or reversal of the profibrotic cell phenotype is an important goal in developing therapeutics for CKD. Nanoparticles offer new ways to deliver antifibrotic therapies to damaged tissues and resident cells to limit manifestation of the profibrotic phenotype.

Methods: We focused on delivering plasmid DNA expressing bone morphogenetic protein 7 (BMP7) or hepatocyte growth factor (HGF)-NK1 (HGF/NK1) by encapsulation within chitosan nanoparticles coated with hyaluronan, to safely administer multifunctional nanoparticles containing the plasmid DNA to the kidneys for localized and sustained expression of antifibrotic factors. We characterized and evaluated nanoparticles for biocompatibility and antifibrotic function. To assess antifibrotic activity , we used noninvasive delivery to unilateral ureteral obstruction mouse models of CKD.

Results: Synthesis of hyaluronan-coated chitosan nanoparticles containing plasmid DNA expressing either BMP7 or NGF/NKI resulted in consistently sized nanoparticles, which-following endocytosis driven by CD44 cells-promoted cellular growth and inhibited fibrotic gene expression . Intravenous tail injection of these nanoparticles resulted in approximately 40%-45% of gene uptake in kidneys . The nanoparticles attenuated the development of fibrosis and rescued renal function in unilateral ureteral obstruction mouse models of CKD. Gene delivery of reversed the progression of fibrosis and regenerated tubules, whereas delivery of halted CKD progression by eliminating collagen fiber deposition.

Conclusions: Nanoparticle delivery of conveyed potent antifibrotic and proregenerative effects. Overall, this research provided the proof of concept on which to base future investigations for enhanced targeting and transfection of therapeutic genes to kidney tissues, and an avenue toward treatment of CKD.
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http://dx.doi.org/10.1681/ASN.2019111160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609017PMC
October 2020

A nitric oxide-releasing hydrogel for enhancing the therapeutic effects of mesenchymal stem cell therapy for hindlimb ischemia.

Acta Biomater 2020 09 11;113:289-304. Epub 2020 Jul 11.

Nankai University School of Medicine, 94 Weijin Road, Tianjin, China; State Key Laboratory of Medicinal Chemical Biology, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, the College of Life Sciences, 94 Weijin Road, Tianjin 300071, China; State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, China; Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, Henan 453003, China. Electronic address:

Therapeutic angiogenesis with mesenchymal stem cells (MSCs) is promising for the clinical treatment of peripheral artery disease (PAD). However, the heterogeneous proangiogenic nature of MSCs is a key challenge in developing more effective treatments with MSCs for therapeutic angiogenesis purposes. Here, we propose to enhance the therapeutic function of human placenta-derived MSCs (hP-MSCs) in hindlimb ischemia therapy by using nitric oxide (NO)-releasing chitosan hydrogel (CS-NO). Our data showed that the co-transplantation of CS-NO hydrogel with hP-MSCs remarkably improved the grafting of hP-MSCs and ameliorated the functional recovery of ischemic hindlimbs. Moreover, we found that the neovascularization of damaged hindlimbs was significantly increased after co-transplanting CS-NO hydrogel and hP-MSCs, as confirmed by bioluminescence imaging (BLI). Further analysis revealed an endothelial-like status transformation of hP-MSCs in the presence of NO, which was identified as a potential mechanism contributing to the enhanced endothelium-protective and proangiogenic capacities of hP-MSCs that promote angiogenesis in mouse models of hindlimb ischemia. In conclusion, this study provides a promising approach for using NO hydrogel to improve the proangiogenic potency of MSCs in ischemic diseases, and the strategy used here facilitates the development of controlled-release scaffolds for enhancing the therapeutic efficiency of MSCs in angiogenic therapy. STATEMENT OF SIGNIFICANCE: The heterogeneous proangiogenic nature of mesenchymal stem cells (MSCs) is a key challenge in developing more effective treatments with MSCs for therapeutic angiogenesis purposes. In this study, we investigated whether nitric oxide (NO)-releasing chitosan hydrogel (CS-NO) could improve the proangiogenic potency of MSCs in ischemic diseases. Our results revealed an endothelial-like status transformation of human placenta-derived MSCs (hP-MSCs) in the presence of NO, which was identified as a potential mechanism contributing to the enhanced endothelium-protective and proangiogenic capacities of hP-MSCs that promote angiogenesis in mouse models of hindlimb ischemia. The strategy for enhancing the pro-angiogenic activity of MSCs with biomaterials provides a practical idea for overcoming the challenges associated with the clinical application of MSCs in therapeutic angiogenesis.
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http://dx.doi.org/10.1016/j.actbio.2020.07.011DOI Listing
September 2020

AIEgen-coupled upconversion nanoparticles eradicate solid tumors through dual-mode ROS activation.

Sci Adv 2020 06 26;6(26):eabb2712. Epub 2020 Jun 26.

Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117585, Singapore.

Reactive oxygen species (ROS) are essential for the regulation of antitumor immune responses, where they could induce immunogenic cell death, promote antigen presentation, and activate immune cells. Here, we report the development of near-infrared (NIR)-driven immunostimulants, based on coupling upconversion nanoparticles with aggregation-induced emission luminogens (AIEgens), to integrate the immunological effects of ROS for enhanced adaptive antitumor immune responses. Intratumorally injected AIEgen-upconversion nanoparticles produce high-dose ROS under high-power NIR irradiation, which induces immunogenic cell death and antigen release. These nanoparticles can also capture the released antigens and deliver them to lymph nodes. Upon subsequent low-power NIR treatment of lymph nodes, low-dose ROS are generated to further trigger efficient T cell immune responses through activation of dendritic cells, preventing both local tumor recurrence and distant tumor growth. The utility of dual-mode pumping power on AIEgen-coupled upconversion nanoparticles offers a powerful and controllable platform to activate adaptive immune systems for tumor immunotherapy.
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http://dx.doi.org/10.1126/sciadv.abb2712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319755PMC
June 2020

Delivery of MSCs with a Hybrid β-Sheet Peptide Hydrogel Consisting IGF-1C Domain and D-Form Peptide for Acute Kidney Injury Therapy.

Int J Nanomedicine 2020 17;15:4311-4324. Epub 2020 Jun 17.

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing 100039, People's Republic of China.

Purpose: By providing a stem cell microenvironment with particular bioactive constituents in vivo, synthetic biomaterials have been progressively successful in stem cell-based tissue regeneration by enhancing the engraftment and survival of transplanted cells. Designs with bioactive motifs to influence cell behavior and with D-form amino acids to modulate scaffold stability may be critical for the development and optimization of self-assembling biomimetic hydrogel scaffolds for stem cell therapy.

Materials And Methods: In this study, we linked naphthalene (Nap) covalently to a short D-form peptide (Nap-FFG) and the C domain of insulin-like growth factor-1 (IGF-1C) as a functional hydrogel-based scaffolds, and we hypothesized that this hydrogel could enhance the therapeutic efficiency of human placenta-derived mesenchymal stem cells (hP-MSCs) in a murine acute kidney injury (AKI) model.

Results: The self-assembling peptide was constrained into a classical β-sheet structure and showed hydrogel properties. Our results revealed that this hydrogel exhibited increased affinity for IGF-1 receptor. Furthermore, cotransplantation of the β-IGF-1C hydrogel and hP-MSCs contributed to endogenous regeneration post-injury and boosted angiogenesis in a murine AKI model, leading to recovery of renal function.

Conclusion: This hydrogel could provide a favorable niche for hP-MSCs and thereby rescue renal function in an AKI model by promoting cell survival and angiogenesis. In conclusion, by covalently linking the desired functional groups to D-form peptides to create functional hydrogels, self-assembling β-sheet peptide hydrogels may serve as a promising platform for tissue-engineering and stem cell therapy.
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http://dx.doi.org/10.2147/IJN.S254635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306577PMC
August 2020

Superhydrophilic fluorinated polymer and nanogel for high-performance F magnetic resonance imaging.

Biomaterials 2020 10 17;256:120184. Epub 2020 Jun 17.

Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, PR China. Electronic address:

F magnetic resonance imaging (F MRI), a kind of non-invasive and non-radioactive diagnostic technique with no endogenous background signals, opens up new research avenues for accurate molecular imaging studies. However, F MRI is manily limited by the performance of contrast agents. Here, for the first time, we presented the zwitterionic fluorinated polymer and nanogel as new types of superhydrophilic, sensitive and ultra-stable F MRI contrast agents. The superhydrophilicity of carboxybetaine zwitterionic structure completely overcame the hydrophobic aggregation-induced signal attenuation associated with amphiphilic fluorinated polymer-based nanoprobes. In addition, the superhydrophilic contrast agent exhibited distinct advantages, including high F-content (19.1 wt%), superior resistance to protein adsorption, constant MR properties and F MRS-based quantitative determination in complex biological fluids, and intense F MRI signals in the whole-body images after intravenous injection. In combination with angiogenesis targeting ligand, the superhydrophilic contrast agent was applied for the unambiguous detection of tumor. Importantly, computational algorithm was established for the directly quantitative determination of bioavailability and tumor-to-whole body ratio (TBR) from the in vivoF MRI dataset, providing real-time information with non-invasive manner. Finally, crosslinked nanogels were developed with significantly prolonged systemic circulation, of which intense F MRI signals nonspecifically distributed in the aortaventralis and blood-rich organs, instead of being trapped steadily in liver as with the state-of-the-art superhydrophobic perfluocarbon nanoemulsions. Overall, this kind of superhydrophilic, zwitterionic fluorinated polymer and nanogel could be defined as a new generation of high-performance F MRI contrast agents, which hold great potential for image-based unambiguous disease detection and computational quantification.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120184DOI Listing
October 2020

Cascade of reactive oxygen species generation by polyprodrug for combinational photodynamic therapy.

Biomaterials 2020 10 18;255:120210. Epub 2020 Jun 18.

Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China. Electronic address:

The redox status of cancer cells is well regulated by the balance between the reactive oxygen species (ROS) generation and elimination. Thus, the overall elevation of ROS level above the cellular tolerability threshold would lead to apoptotic or necrotic cell death. Herein, cinnamaldehyde (CA), a kind of oxidative stress amplified agent, was combined with photosensitizer pheophorbide A (PA) to promote the generation of ROS though synergistically endogenous and exogenous pathways. Firstly, acid-responsive polygalactose-co-polycinnamaldehyde polyprodrug (termed as PGCA) was synthesized, which could self-assemble into stable nanoparticles for the delivery of PA (termed as [email protected] NPs). The abundant expression of galactose receptor on tumor cells facilitated the positive targeting and cellular uptake efficiency of [email protected] NPs, after which PA could be synchronously released in company with the intracellular disassembly of PGCA NPs, due to the detaching of CA moieties under acidic microenvironment in endo/lysosomal compartment. Significantly increased ROS level was induced by the combined action of CA and PA with light irradiation, resulting in dramatically enhanced apoptosis of cancer cells. Importantly, intravenous injection of [email protected] NPs potently inhibited the tumor growth in hepatocellular carcinoma with negligible adverse effects. Moreover, combined with anti-programmed cell death protein 1 (anti-PD-1) therapy, [email protected] NPs treatment elicited anti-melanoma T-cell immune response and significantly promoted T cells infiltration in tumors. Hence, this novel polyprodrug nano delivery system was able to target and modulate the unique redox regulatory mechanisms of cancer cells through endogenous and exogenous pathways, providing a feasible approach to achieve synergetic therapeutic activity and selectivity.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120210DOI Listing
October 2020

Construction and application of therapeutic metal-polyphenol capsule for peripheral artery disease.

Biomaterials 2020 10 15;255:120199. Epub 2020 Jun 15.

Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, PR China. Electronic address:

Lesions of patients with peripheral artery disease (PAD) are in a harmful microenvironment, which features increased oxidative stress and inflammatory infiltration. Hence, it is essential to improve the microenvironment along with angiogenesis. In this study, metal-polyphenol capsules (Cu-EGCG), which combines the therapeutic anti-inflammatory and antioxidant activities of EGCG and the angiogenic activity of copper ions, were synthesized through coordination between EGCG and copper ions. The sustained release of the copper ions from Cu-EGCG was demonstrated in vitro, and biocompatible Cu-EGCG can scavenge intracellular ROS, reduce cell death in the presence of cytotoxic levels of ROS, and decrease the expression of pro-inflammatory cytokines (TNF-α, IL-6). Moreover, Cu-EGCG induced the secretion of vascular endothelial growth factor (VEGF) in a hindlimb ischaemia model of PAD. More importantly, the upregulated expression of platelet endothelial cell adhesion molecule-1 (CD31) and proliferating cell nuclear antigen (PCNA) in ischaemic tissues indicated the remarkable effect of Cu-EGCG on angiogenesis. In addition, Cu-EGCG showed significant blood recovery in ischaemic hindlimbs. Taking these results together, biocompatible Cu-EGCG with therapeutic functions holds great potential applications for PAD therapy.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120199DOI Listing
October 2020

Targeted Repair of Vascular Injury by Adipose-Derived Stem Cells Modified with P-Selectin Binding Peptide.

Adv Sci (Weinh) 2020 Jun 22;7(11):1903516. Epub 2020 Apr 22.

Key Laboratory of Bioactive Materials Ministry of Education College of Life Sciences Nankai University Tianjin 300071 China.

Percutaneous coronary intervention for coronary artery disease treatment often results in pathological vascular injury, characterized by P-selectin overexpression. Adipose-derived stem cells (ADSCs) therapeutic efficacy remains elusive due to poor ADSCs targeting and retention in injured vessels. Here, conjugated P-selectin binding peptide (PBP) to polyethylene glycol-conjugated phospholipid derivative (DMPE-PEG) linkers (DMPE-PEG-PBP; DPP) are used to facilitate the modification of PBP onto ADSCs cell surfaces via hydrophobic interactions between DMPE-PEG and the phospholipid bilayer. DPP modification neither has influence on ADSCs proliferation nor apoptosis/paracrine factor gene expression. A total of 5 × 10 m DPP-modified ADSCs (DPP-ADSCs) strongly binds to P-selectin-displaying activated platelets and endothelial cells (ECs) in vitro and to wire-injured rat femoral arteries when administered by intra-arterial injection. Targeted binding of ADSCs shields injury sites from platelet and leukocyte adhesion, thereby decreasing inflammation at injury sites. Furthermore, targeted binding of ADSCs recovers injured ECs functionality and reduces platelet-initiated vascular smooth muscle cells (VSMCs) chemotactic migration. Targeted binding of DPP-human ADSCs to balloon-injured human femoral arteries is also demonstrated in ex vivo experiments. Overall, DPP-ADSCs promote vascular repair, inhibit neointimal hyperplasia, increase endothelium functionality, and maintain normal VSMCs alignment, supporting preclinical noninvasive utilization of DPP-ADSCs for vascular injury.
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http://dx.doi.org/10.1002/advs.201903516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284211PMC
June 2020
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