首页期刊导航|Acta biomaterialia
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Acta biomaterialia
Elsevier
Acta biomaterialia

Elsevier

1742-7061

Acta biomaterialia/Journal Acta biomaterialiaEIISTPSCI
正式出版
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    Impact of PEGylation on an antibody-loaded nanoparticle-based drug delivery system for the treatment of inflammatory bowel disease

    Xu Y.Prevost J.R.C.McCartney F.Brayden D....
    12页
    查看更多>>摘要：? 2021 Acta Materialia Inc.Nanoparticle-based oral drug delivery systems have the potential to target inflamed regions in the gastrointestinal tract by specifically accumulating at disrupted colonic epithelium. But, delivery of intact protein drugs at the targeted site is a major challenge due to the harsh gastrointestinal environment and the protective mucus layer. Biocompatible nanoparticles engineered to target the inflamed colonic tissue and efficiently penetrate the mucosal layer can provide a promising approach for orally delivering monoclonal antibodies to treat inflammatory bowel disease. The study aims to develop mucus-penetrating nanoparticles composed of poly(lactic-co-glycolic acid, PLGA) polymers with two different polyethylene glycol (PEG) chain lengths (2 kDa and 5kDa) to encapsulate monoclonal antibody against tumor necrosis factor-α (TNF-α). The impact of different PEG chain lengths on the efficacy of the nanosystems was evaluated in vitro, ex vivo, and in vivo. Both PLGA-PEG2k and PLGA-PEG5k nanoparticles successfully encapsulated the antibody and significantly reduced TNF-α secretion from activated macrophages and intestinal epithelial cells. However, only antibody-loaded PLGA-PEG2k nanoparticles were able to alleviate the experimental acute colitis in mice demonstrated by improved colon weight/length ratio, histological score, and reduced tissue-associated myeloperoxidase activity and expression of proinflammatory cytokine TNF-α levels compared with the control group. The results suggest that despite having no significant differences in the in vitro cell-based assays, PEG chain length has a significant impact on the in vivo performance of the mucus penetrating nanoparticles. Overall, PLGA-PEG2k nanoparticles were presented as a promising oral delivery system for targeted antibody delivery to treat inflammatory bowel disease. Statement of significance: There is an unmet therapeutic need for oral drug delivery systems for safe and effective antibody therapy of inflammatory bowel disease. Therefore, we have developed PEGylated PLGA-based nanoparticulate drug delivery systems for oral targeted delivery of anti-TNF-α antibody as a potential alternative treatment strategy. The PEG chain length did not affect encapsulation efficiency or interaction with mucin in vitro but resulted in differences in in vitro release profile and in vivo efficacy study. We demonstrated the superiority of anti-TNF-α mAb-PLGA-PEG2k over mAb-PLGA-PEG5k nanoparticles to effectively exhibit anti-inflammatory responses in an acute murine colitis model. These nanoparticle-based formulations may be adjusted to encapsulate other drugs that could be applied to a number of disorders at different mucosal surfaces.
      原文链接:
    • NSTL
    • Elsevier

    Targeted delivery of PARP inhibitors to neuronal mitochondria via biomimetic engineered nanosystems in a mouse model of traumatic brain injury

    Sun J.Liu J.Gao C.Zheng J....
    13页
    查看更多>>摘要：? 2021 Acta Materialia Inc.Traumatic brain injury (TBI) is known to activate poly (ADP-ribose) polymerase (PARP-1), which leads to pronounced negative effects on mitochondrial DNA (mt-DNA) repair and function. Notably, PARP inhibitors are reported to be beneficial in experimental models of TBI. A targeting strategy for the delivery of neuronal mitochondria-specific PARP inhibitors could result in a greater neuroprotective effect and be a safer approach for TBI treatment. In the present study, we developed the PARP inhibitor olaparib (Ola) as a model drug and devised red blood cell (RBC)-coated nanostructured lipid carriers (RBCNLCs) co-modified with C3 and SS31 peptide (C3/SS31-RBCNLCs) for brain neuronal mitochondria-targeting. Our results indicated that biomimetic nanosystems have the physical and chemical properties of the NLCs, as well as the biological properties of RBC. A high concentration of Ola delivered into brain mitochondria by C3/SS31-RBCNLCs-Ola effectively improved mitochondrial function and prevented neuronal cell death caused by excessive activation of injury-induced mitochondrial PARP (mt-PARP) in vitro and in vivo. Taken together, the results of this study support the preclinical feasibility of developing highly effective nano-drugs as part of precision medicine for TBI. Statement of Significance: TBI-induced neuronal mitochondria DNA damage activates Poly(ADP-ribose) Polymerase (PARP1) which leads to a pronounced negative effect on mitochondrial DNA repair and mitochondrial function. In recent years, PARP inhibitors showed strong benefits in experimental models of TBI, more importantly PARP inhibitors specially target neuronal mitochondria may play a greater neuroprotective role and may be a safer approach for TBI treatment. Herein, we designed red blood cell (RBC) membrane-coated nanostructure lipid carriers dual-modified with C3 and SS31 (C3/SS31-RBCNLCs) to accomplish these objectives. After encapsulating Olaparib (Ola) as the model PARP inhibitor, the data demonstrated that C3/SS31-RBCNLCs, with brain neuronal mitochondria targeting, can reduce neuronal cell death and improve mitochondrial dysfunction triggered by mitochondrial PARP activation in vitro and in vivo.
      原文链接:
    • NSTL
    • Elsevier

    Covalent coupling of HIV-1 glycoprotein trimers to biodegradable calcium phosphate nanoparticles via genetically encoded aldehyde-tags

    Damm D.Kostka K.Weingartner C.Wagner J.T....
    15页
    查看更多>>摘要：? 2021The usage of antigen-functionalized nanoparticles has become a major focus in the field of experimental HIV-1 vaccine research during the last decade. Various molecular mechanisms to couple native-like trimers of the HIV-1 envelope protein (Env) onto nanoparticle surfaces have been reported, but many come with disadvantages regarding the coupling efficiency and stability. In this study, a short amino acid sequence (“aldehyde-tag”) was introduced at the C-terminus of a conformationally stabilized native-like Env. The post-translational conversion of a tag-associated cysteine to formylglycine creates a site-specific aldehyde group without alteration of the Env antigenicity. This aldehyde group was further utilized for bioconjugation of Env trimers. We demonstrated that the low acidic environment necessary for this bioconjugation is not affecting the trimer conformation. Furthermore, we developed a two-step coupling method for pH-sensitive nanoparticles. To this end, we conjugated aldehyde-tagged Env with Propargyl-PEG3-aminooxy linker (oxime ligation; Step-one) and coupled these conjugates by copper-catalyzed azide-alkyne cycloaddition (Click reaction; Step-two) to calcium phosphate nanoparticles (CaPs) functionalized with terminal azide groups. CaPs displaying orthogonally arranged Env trimers on their surface (o-CaPs) were superior in activation of Env-specific B-cells (in vitro) and induction of Env-specific antibody responses (in vivo) compared to CaPs with Env trimers coupled in a randomly oriented manner. Taken together, we present a reliable method for the site-specific, covalent coupling of HIV-1 Env native-like trimers to the surface of nanoparticle delivery systems. This method can be broadly applied for functionalization of nanoparticle platforms with conformationally stabilized candidate antigens for both vaccination and diagnostic approaches. Statement of significance: During the last decade antigen-functionalized nanoparticles have become a major focus in the field of experimental HIV-1 vaccines. Rational design led to the production of conformationally stabilized HIV-1 envelope protein (Env) trimers - the only target for the humoral immune system. Various molecular mechanisms to couple Env trimers onto nanoparticle surfaces have been reported, but many come with disadvantages regarding the coupling efficiency and stability. In this paper, we describe a highly selective bio-conjugation of Env trimers to the surface of medically relevant calcium phosphate nanoparticles. This method maintains the native-like protein conformation and has a broad potential application in functionalization of nanoparticle platforms with stabilized candidate antigens (including stabilized spike proteins of coronaviruses) for both vaccination and diagnostic approaches.
      原文链接:
    • NSTL
    • Elsevier

    A generic self-assembly approach towards phototheranostics for NIR-II fluorescence imaging and phototherapy

    Cui C.Wang C.Fu Q.Song J....
    9页
    查看更多>>摘要：? 2021 Acta Materialia Inc.Controllable self-assembly of photonic molecules for precise biomedicine is highly desirable but challenging to prepare multifunctional nano-phototheranostics. Herein, we developed a generic self-assembly approach to design nano-phototheranostics that provides NIR-II fluorescence imaging and phototherapy. We first designed and synthesized two amphiphilic photonic molecules, PEG2000-IR806 and BODIPY. Then, we prepared the co-self-assembled phototheranostic agents, PEG2000-IR806/BODIPY nanoparticles (PIBY NPs). The morphology of the PIBY NPs is controllable by adjusting the ratio of PEG2000-IR806 and BODIPY during self-assembly. The NIR-II fluorescence properties and phototherapy capability of the PIBY NPs were demonstrated in vitro and in vivo. By tuning the ratio of PEG2000-IR806 and BODIPY, the PIBY NPs showed various morphologies (e.g. spherical nanoparticles, nanovesicles and rod-like nanoparticles). The PEG2000-IR806 plays two roles in the co-self-assemblies, one is second near-infrared (NIR-II, 1000–1700 nm) agent, the other is the surfactant for BODIPY encapsulation. The phototherapeutic PIBY NPs all show bright NIR-II fluorescence and effective phototherapeutic (photothermal and photodynamic) properties, which are attributed to IR806 and BODIPY, respectively. The driving force of the self-assembly can be attributed to the electrostatic interaction between NIR806 and BODIPY and their hydrophobicity. The rod-like PIBY NPs (rPIBY NPs) demonstrated a low half inhibitory concentration (IC50) of 3.96 μg/mL on U87MG cells. The NIR-II imaging showed the accumulation of rPIBY NPs in the tumor region. After systemic injection of rPIBY NPs at low dose (0.5 mg/kg), the tumor growth was greatly inhibited upon laser irradiation without noticeable side effects. This study provides a generic self-assembly approach to fabricate NIR-II imaging and phototherapeutic platform for cancer phototheranostics. Statement of significance: Nanophototheranostics providing NIR-II fluorescence imaging and phototherapy are expected to play a critical role in modern precision medicine. Controllable self-assembly of optical molecules for the fabrication of efficient nanophototheranostics is highly desirable but challenging. This work reports for the first time the co-assembly of a NIR-II imaging contrast agent and a phototherapeutic agent to yield nanophototheranostics with various morphologies. The design of molecular co-assembly with complementary optical functions can be a generic method for future the development of phototheranostics.
      原文链接:
    • NSTL
    • Elsevier

    Schwann cell-derived EVs facilitate dental pulp regeneration through endogenous stem cell recruitment via SDF-1/CXCR4 axis

    Pan J.Tian W.Wang D.Lyu Y....
    15页
    查看更多>>摘要：? 2021The dental pulp is critical for physiological vitality of the tooth, and dental pulp regeneration has great potential for rebuilding live pulp tissue after pulp disease. Schwann cells (SCs) play a critical role in the support, maintenance, and regeneration of nerve fibers in dental pulp. Extracellular vesicles (EVs), which possess cell homing and tissue repair potential, derived from SCs (SC-EVs), can regulate dental mesenchymal stem cells (MSCs) proliferation, multipotency, and self-renewal. However, the role of SC-EVs in dental pulp tissue regeneration remains unclear. To address this question, we treated dental pulp stem cells (DPSCs) and bone marrow stem cells (BMSCs) with SC-EVs, and the results showed an obvious increase in the proliferation, migration, and osteogenic differentiation of both cell types. SC-EVs also promoted neurite outgrowth and neuron migration of rat dorsal root ganglia, as well as vessel formation in vitro. In an in vivo model of subcutaneous, SC-EVs enhanced the recruitment of endogenous vascular endothelioid-like cells and MSCs, and promoted the formation of a pulpo-dentinal complex-like structure. Finally, mass spectrometry analyses and western blot revealed that stromal cell-derived factor 1 (SDF-1, also known as CXCL12) plays a dominant role in SC-EVs. Together, these data suggest that SC-EVs successfully recruit endogenous stem cells to promote dental pulp regeneration. Our results provide a cell-free strategy for pulp regeneration that avoids the risks associated with stem cell transplantation. Statement of Significance: Dental pulp is vulnerable to infections resulting from dental care, trauma, and multiple restorations, with such infections resulting in pulpitis and pulp necrosis. The current endodontic treatment of irreversible pulp disease cannot restore the function of dental pulp and tissue engineering strategies using cell-based approaches are limited by several disadvantages, including immune rejection and limited cell sources. In this study, we found that schwann cells-derived EVs facilitated dental pulp regeneration through endogenous stem cells recruitment via SDF-1/CXCR4 axis without exogenous cell transplantation. We believe that our study makes a significant contribution to describe a cell-free strategy to promote dental pulp regeneration.
      原文链接:
    • NSTL

    Rescuing ischemic stroke by biomimetic nanovesicles through accelerated thrombolysis and sequential ischemia-reperfusion protection

    Yu W.Yin N.Yang Y.Xuan C....
    16页
    查看更多>>摘要：? 2021Rational design of nanomedicine to accelerate thrombolysis and sequentially avoid thrombolysis-mediated reperfusion injury is still a challenge. Here, we develop a biomimetic nanovesicle (tPA/MNP@PM, tMP) by simple encapsulating melanin nanoparticles (MNP) and tPA with a platelet membrane vesicle (PM), which integrates the thrombus targeting property of PM, the photothermal conversion performance and free radical scavenging property of natural melanin for cascaded ischemic stroke treatment. Benefiting from natural thrombus-targeted adhesion capability of PM, nanovesicles could efficiently target thrombus site. Then near-infrared (NIR) mediated photothermal of MNP could lead to rupture of nanovesicles, thus achieving precise release of tPA in thrombus. Interestingly, local hyperthermia also increases the activity of tPA for accelerating thrombolysis. Afterwards, site specific released MNP (4.5 nm) accompanied by hemoperfusion can cross the BBB and accumulate in cerebral ischemia site, scavenging various free radicals and suppressing inflammation- and immune response–induced injury to achieve neuroprotection after thrombolysis. In addition, the biomimetic nanovesicle could block tPA-induced brain hemorrhage after stroke to improve thrombolytic therapy. The evaluation in ischemic stroke mice confirmed that the simple-prepared nanomedicine with cascaded thrombus targeting, precise thrombolysis and ischemia-reperfusion protection properties can significantly enhance the treatment effect of ischemic stroke. Statement of significance: Ischemic stroke is recognized as a leading cause of death and disability in the world. Rational design of nanomedicine to accelerate thrombolysis and sequentially avoid thrombolysis-mediated reperfusion injury is still a challenge. Herein, a biomimetic nanovesicle (tMP) was developed for sequential ischemic stroke treatment. It could overcome the drawbacks of free tPA for safe thrombolysis: i) platelet membrane biomimetic coating significantly increases thrombus targeting; ii) NIR-mediated photothermal of natural melanin precise controlled release of tPA in thrombus in situ, and local hyperthermia also increases the thrombolytic activity of tPA. Notably, released melanin nanoparticles (4.5 nm) accompanied by hemoperfusion can across BBB and avoid ischemia-reperfusion injury through free radical scavenging and inflammation/immune response suppression.
      原文链接:
    • NSTL
    • Elsevier

    Small extracellular vesicles from hypoxic mesenchymal stem cells alleviate intervertebral disc degeneration by delivering miR-17-5p

    Zhou Z.-M.Bao J.-P.Peng X.Gao J.-W....
    18页
    查看更多>>摘要：? 2021 Acta Materialia Inc.Minimally invasive repair strategies are a very promising approach for the treatment of intervertebral disc degeneration (IDD). In recent years, small extracellular vesicles (sEVs) secreted from mesenchymal stem cells (MSCs) have been shown great potential in alleviating IDD. However, in vitro experiments, MSCs are usually exposed to a normoxic micro-environment, which differs greatly from the hypoxic micro-environment in vivo. The primary purpose of our research was to determine whether sEVs isolated from MSCs under hypoxic status (H-sEVs) exhibit a more beneficial effect on protecting IDD compared with sEVs derived from MSCs under normoxic status (N-sEVs). A tail IDD rat model and a series of experiments in vitro were conducted to compare the beneficial effects of PBS, N-sEVs, and H-sEVs treatment. Then, to validate the role of sEVs miRNAs in IDD, a miRNA microarray sequencing analysis and a series of rescue experiments were conducted. Luciferase activity, RNA-ChIP and western blot were performed to explore the potential mechanisms. The results indicate that sEVs alleviate IDD by ameliorating the homeostatic imbalance between anabolism and catabolism in vivo and in vitro. Microarray sequencing result shows that miR-17-5p is maximally enriched in H-sEVs. Toll-like receptor 4 (TLR4) was determined to be a target downstream gene of miR-17-5p. Finally, it was found that H-sEVs miR-17-5p may modulate proliferation and synthesis of human nucleus pulposus cells (HNPCs) matrix via TLR4 pathway. In conclusion, H-sEVs miR-17-5p alleviate IDD via promoting HNPCs matrix proliferation and synthesis, providing new therapeutic targets for IDD. Statement of significance: Intervertebral disc degeneration (IDD) is the primary cause of low back pain (LBP), which is a huge burden to society. Our research demonstrates for the first time that hypoxic pretreatment of small extracellular vesicles (H-sEVs) effectively alleviated the progress of IDD. In short, in the present research, we found that H-sEVs miR-17-5p could modulate proliferation and synthesis of nucleus pulposus cells (NPCs) matrix via TLR4/PI3K/AKT pathway. Therefore, hypoxic pre-treatment is a prospective and efficient method to optimize the therapeutic effect of MSCs-derived sEVs. miRNA and MSCs-derived sEVs combination may be a promising therapeutic approach for IDD.
      原文链接:
    • NSTL
    • Elsevier

    Extracellular vesicles derived from starving BMSCs enhance survival of chondrocyte aggregates in grafts by attenuating chondrocyte apoptosis and enabling stable cartilage regeneration for craniofacial reconstruction

    Yuan P.Li Z.Shao B.Zeng T....
    15页
    查看更多>>摘要：? 2021The improvement of cell survival in cartilage tissue engineering remains a challenge, especially for large-sized, specifically shaped cartilage grafts used in reconstructing craniofacial defects. In this study, we found that bone marrow mesenchymal stem cells (BMSCs) pre-conditioned in a starving environment enhanced the anti-apoptosis potential of co-transplanted chondrocytes, which significantly enhanced their survival rates before host nutrition was resumed. Further examination revealed that extracellular vesicles (EVs) derived from starving BMSCs played essential roles in ameliorating apoptosis and regulating autophagy of chondrocytes, thereby enhancing the survival of cultured chondrocytes. In vivo studies demonstrated that EVs derived from starving BMSCs significantly improved the survival of chondrocyte bricks, which confirmed the effects of nasal augmentation. These pre-treated chondrocyte bricks showed continuous cartilage growth in vivo and acquired chondrogenesis comparable to that following the chondrocyte-BMSC co-transplantation approach. This study provided new insights on how BMSC-derived EVs improved cartilage reconstruction in the craniofacial regions and offered a new approach for regenerating cartilaginous organs based on cell macroaggregates. Statement of significance: The use of extracellular vesicles (EVs) of mesenchymal stem cells has been considered as a promising approach in cartilage tissue engineering. In the present study, for the first time, we investigated the protective effect of EVs secreted by starving bone marrow mesenchymal stem cells (BMSCs) on chondrocytes in vitro and in vivo. The results demonstrated that EVs secreted by starving BMSCs inhibited chondrocyte apoptosis and chondrocyte autophagy through many microRNAs, thereby improving the survival of grafts. Transcriptomic analysis revealed the potential mechanisms of this protective effect.
      原文链接:
    • NSTL
    • Elsevier

    Transepithelial delivery of insulin conjugated with phospholipid-mimicking polymers via biomembrane fusion-mediated transcellular pathways

    Hatano H.Meng F.Sakata M.Matsumoto A....
    12页
    查看更多>>摘要：? 2021 Acta Materialia Inc.Epithelial barriers that seal cell gaps by forming tight junctions to prevent the free permeation of nutrients, electrolytes, and drugs, are essential for maintaining homeostasis in multicellular organisms. The development of nanocarriers that can permeate epithelial tissues without compromising barrier function is key for establishing a safe and efficient drug delivery system (DDS). Previously, we have demonstrated that a water-soluble phospholipid-mimicking random copolymer, poly(2-methacryloyloxyethyl phosphorylcholine30-random-n?butyl methacrylate70) (PMB30W), enters the cytoplasm of live cells by passive diffusion manners, without damaging the cell membranes. The internalization mechanism was confirmed to be amphiphilicity-induced membrane fusion. In the present study, we demonstrated energy-independent permeation of PMB30W through the model epithelial barriers of Madin-Darby canine kidney (MDCK) cell monolayers in vitro. The polymer penetrated epithelial MDCK monolayers via transcellular pathways without breaching the barrier functions. This was confirmed by our unique assay that can monitor the leakage of the proton as the smallest indicator across the epithelial barriers. Moreover, energy-independent transepithelial permeation was achieved when insulin was chemically conjugated with the phospholipid-mimicking nanocarrier. The bioactivity of insulin as a growth factor was found to be maintained even after translocation. These fundamental findings may aid the establishment of transepithelial DDS with advanced drug efficiency and safety. Statement of significance: A nanocarrier that can freely permeate epithelial tissues without compromising barrier function is key for successful DDS. Existing strategies mainly rely on paracellular transport associated with tight junction breakdown or transcellular transport via transporter recognition-mediated active uptake. These approaches raise concerns about efficiency and safety. In this study, we performed non-endocytic permeation of phospholipid-mimicking polymers through the model epithelial barriers in vitro. The polymer penetrated via transcytotic pathways without breaching the barriers of biomembrane and tight junction. Moreover, transepithelial permeation occurred when insulin was covalently attached to the nanocarrier. The bioactivity of insulin was maintained even after translocation. The biomimetic design of nanocarrier may realize safe and efficient transepithelial DDS.
      原文链接:
    • NSTL
    • Elsevier

    Stimuli-responsive, dual-function prodrug encapsulated in hyaluronic acid micelles to overcome doxorubicin resistance

    Qiu L.Xu J.Ahmed K.S.Zhu M....
    14页
    查看更多>>摘要：? 2021Multidrug resistance (MDR) is the main challenge faced by cancer chemotherapy. Drug-conjugate offers a promising strategy for breast cancer therapy. In this regard, we developed a DNVM multifunctional drug delivery system by crosslinking doxorubicin (DOX) and vitamin E succinate (VES) with a pH-sensitive hydrazone bond and then encapsulated the DOX-NN-VES prodrug into pH-sensitive hyaluronic acid-2-(octadecyloxy)-1,3-dioxan-5-amine (HOD) micelles. DOX resistant MCF-7/ADR cell were adopted as a model to study the capability and mechanism of MDR reversal. DNVM exhibited much higher cytotoxicity and cell uptake efficiency compared with that of acid-insensitive DOX-VES loaded HOD micelles (DVSM) and DOX loaded HOD micelles (DOXM), indicating the better capacity of DNVM for the reversal of MDR. Moreover, DNVM prevented drug efflux more effectively, inhibited the expression of P-gp, induced excessive production of reactive oxygen species and affected the expression of apoptosis-related proteins. In vivo experiments showed that DNVM significantly inhibited the tumor growth with no obvious changes in the body weight of MCF-7/ADR cells-bearing nude mice. The results suggested that the “double gain” DNVM can synergistically enhance the efficacy of chemotherapeutics for DOX resistant tumor cells and has the potential to overcome tumor MDR. Statement of Significance: A dual-functional pH-sensitive doxorubicin - vitamin E succinate prodrug was developed and loaded into tumor microenvironment-sensitive hyaluronic acid-2-(octadecyloxy)-1,3-dioxan-5-amine micelle system (DNVM) for sequencing stimuli-release and overcoming doxorubicin resistance. The “double gain” DNVM can synergistically enhance the efficacy of chemotherapeutics for doxorubicin resistant tumor cells and has the potential to overcome tumor multiple drug resistance.
      原文链接:
    • NSTL
    • Elsevier