bims-drudre 2022-01-02 papers

bims-drudre

Biomed News

on Targeted drug delivery and programmed release mechanisms

Issue of 2022–01–02
twenty-one papers selected by
Ceren Kimna, Technical University of Munich

Engineering Supramolecular Nanomedicine for Targeted Near Infrared-triggered Mitochondrial Dysfunction to Potentiate Cisplatin for Efficient Chemophototherapy.
Multistage Systemic and Cytosolic Protein Delivery for Effective Cancer Treatment.
BiTE secretion from in situ-programmed myeloid cells results in tumor-retained pharmacology.
Driving DNA Origami Assembly with a Terahertz Wave.
One-Step Integration of Tumor Microenvironment-Responsive Calcium and Copper Peroxides Nanocomposite for Enhanced Chemodynamic/Ion-Interference Therapy.
DNA Origami-Encoded Integration of Heterostructures.
Rapid Identification of DNA Fragments through Direct Sequencing with Electro-Optical Zero-Mode Waveguides.
Paclitaxel derivative-based liposomal nanoplatform for potentiated chemo-immunotherapy.
Biomaterial-Mediated Presentation of Jagged-1 Mimetic Ligand Enhances Cellular Activation of Notch Signaling and Bone Regeneration.
Self-Delivery Janus-Prodrug for Precise Immuno-Chemotherapy of Colitis-Associated Colorectal Cancer.
Nanovesicle-mediated targeted delivery of immune checkpoint blockades to potentiate therapeutic efficacy and prevent side effects.
Peptide-Decorated DNA Nanostructures Promote Site-Specific Hydroxyapatite Growth.
Suppression of fibrin(ogen)-driven pathologies through controlled knockdown by lipid nanoparticle delivery of siRNA.
Engineered Cell-Secreted Extracellular Matrix Modulates Cell Spheroid Mechanosensing and Amplifies their Response to Inductive Cues for the Formation of Mineralized Tissues.
Highly Transparent and Self-Healable Solar Thermal Anti-/De-Icing Surfaces: When Ultrathin MXene Multilayers Marry Solid Slippery Self-Cleaning Coating.
Semiconducting Polymer Nano-regulators with Cascading Activation for Photodynamic Cancer Immunotherapy.
Concepts and Design of Introducing Synthetic MicroRNAs into Mammalian Cells.
Supramolecular Reinforcement of Polymer-Nanoparticle Hydrogels for Modular Materials Design.
Engineering a Photosynthetic Bacteria-incorporated Hydrogel for Infected Wound Healing.
Mimicking Native Heart Tissue Physiology and Pathology in Silk Fibroin Constructs Through Perfusion-based Dynamic Mechanical Stimulation Microdevice.
Reshaping Tumor Immune Microenvironment Based on Light Activated Nano-Platform for Efficient Cancer Therapy.

ACS Nano. 2021 Dec 28.

Engineering Supramolecular Nanomedicine for Targeted Near Infrared-triggered Mitochondrial Dysfunction to Potentiate Cisplatin for Efficient Chemophototherapy.

Wei Zhang, Xiang-Fu Du, Ben Liu, Cairong Li, Jing Long, Mei-Xia Zhao, Zhenyu Yao, Xing-Jie Liang, Yuxiao Lai.

  Combinatorial cancer therapies based on nanomedicine have emerged as a promising strategy to achieve potentiated treatment efficiency. Herein, cisplatin (CDDP) prodrug (Pt-CD) and a mitochondria-targeted near-infrared (NIR) photosensitizer IR780 were combined to construct a multifunctional nanomedicine IR780@Pt NPs through a supramolecular self-assembly strategy. Targeted mitochondrial dysfunction of cancer cells was sufficiently induced under NIR laser irradiation through both photothermal and photodynamic effects, inhibiting the overactive mitochondrial energy pathways of cancer cells. The mitochondrial dysfunction significantly attenuated the crosstalk between mitochondria and nucleus via the cellular ATP energy chain, leading to obvious down-regulation of the key proteins of the nucleotide excision repair (NER) pathway. Thereby, the chemotherapeutic effect of CDDP could be significantly potentiated because of reduced DNA lesion repair capacity by ERCC1-XPF nuclease system. Moreover, IR780@Pt NPs exhibited excellent NIR fluorescence and photoacoustic (PA) imaging capacity for in vivo imaging-guided NIR laser treatment. Ultimately, the IR780@Pt NPs mediated combinatorial chemophototherapy achieved potentiated anticancer efficacy against cancer cells in vitro and tumor inhibition performance in vivo. Overall, this study highlighted the significance of nanomedicine mediated targeted induction of mitochondrial dysfunction to potentiate chemotherapy for efficient combinatorial cancer therapy.

Keywords:  cisplatin; combinatorial therapy; mitochondrial dysfunction; nanomedicine; supramolecular self-assembly

DOI:  https://doi.org/10.1021/acsnano.1c09555
Nano Lett. 2021 Dec 28.

Multistage Systemic and Cytosolic Protein Delivery for Effective Cancer Treatment.

Liyi Fu, Xianwu Hua, Xingya Jiang, Jinjun Shi.

  Current clinical applications of protein therapy are largely limited to systemically accessible targets in vascular or extracellular areas. Major obstacles to the widespread application of protein therapeutics in cancer treatment include low membrane permeability and endosomal entrapment. Herein, we report a multistage nanoparticle (NP) strategy for systemic and cytosolic protein delivery to tumor cells, by encapsulating a protein conjugate, tetra-guanidinium (TG)-modified saporin, into tumor microenvironment (TME) pH-responsive polymeric NPs. Upon reaching the tumor site after systemic circulation, the polymeric NPs respond rapidly to the acidic tumor microenvironment and release the TG-saporin conjugates, which penetrate the tumor tissue and enter into tumor cells via TG-mediated cytosolic transportation. The TG-saproin NPs showed potent inhibition of lung cancer cell growth in vitro and in vivo. We expect that this multistage NP delivery strategy with long blood circulation, deep tumor penetration, and efficient cytosolic transport may be applicable to various therapeutic proteins for effective cancer treatment.

Keywords:  TME pH-responsive nanoparticle; cytosolic transport; multistage delivery; protein conjugate; tumor penetration

DOI:  https://doi.org/10.1021/acs.nanolett.1c03293
J Control Release. 2021 Dec 23. pii: S0168-3659(21)00682-9. [Epub ahead of print]342 14-25

BiTE secretion from in situ-programmed myeloid cells results in tumor-retained pharmacology.

S Hao, V V Inamdar, E C Sigmund, F Zhang, S B Stephan, C Watson, S J Weaver, U B Nielsen, M T Stephan.

  Bispecific T-Cell Engagers (BiTEs) are effective at inducing remission in hematologic cancers, but their use in solid tumors has been challenging due to their extreme potency and on-target, off-tumor toxicities in healthy tissue. Their deployment against solid tumors is further complicated by insufficient drug penetration, a hostile tumor microenvironment, and immune escape. To address these challenges, we developed targeted nanocarriers that can deliver in vitro-transcribed mRNA encoding BiTEs to host myeloid cells - a cell type that is actively recruited into the tumor microenvironment. We demonstrate in an immunocompetent mouse model of ovarian cancer, that infusion of these nanoparticles directs BiTE expression to tumor sites, which reshapes the microenvironment from suppressive to permissive and triggers disease regression without systemic toxicity. In contrast, conventional injections of recombinant BiTE protein at doses required to achieve anti-tumor activity, induced systemic inflammatory responses and severe tissue damage in all treated animals. Implemented in the clinic, this in situ gene therapy could enable physicians - with a single therapeutic - to safely target tumor antigen that would otherwise not be druggable due to the risks of on-target toxicity and, at the same time, reset the tumor milieu to boost key mediators of antitumor immune responses.

Keywords:  Bi-specific T-cell engagers (BiTEs); In situ gene therapy; Nanotechnology

DOI:  https://doi.org/10.1016/j.jconrel.2021.12.029
Nano Lett. 2021 Dec 30.

Driving DNA Origami Assembly with a Terahertz Wave.

Chao Zhang, Yifang Yuan, Kaijie Wu, Yue Wang, Shitai Zhu, Jiye Shi, Lihua Wang, Qian Li, Xiaolei Zuo, Chunhai Fan, Chao Chang, Jiang Li.

  Terahertz (THz) waves show nontrivial interactions with living systems, but the underlying molecular mechanisms have yet to be explored. Here, we employ DNA origami as a model system to study the interactions between THz waves and DNA structures. We find that a 3-min THz illumination (35.2 THz) can drive the unwinding of DNA duplexes at ∼10 °C below their melting point. Computational study reveals that the THz wave can resonate with the vibration of DNA bases, provoking the hydrogen bond breaking. The cooperation of thermal and nonthermal effects allows the unfolding of undesired secondary structures and the THz illumination can generate diverse DNA origami assemblies with the yield (>80%) ∼ 4-fold higher than that by the contact heating at similar temperatures. We also demonstrate the in situ assembly of DNA origami in cell lysate. This method enables remotely controllable assembly of intact biomacromolecules, providing new insight into the bioeffects of THz waves.

Keywords:  DNA origami; in situ assembly; near-physiological environments; nonthermal effect; terahertz illumination

DOI:  https://doi.org/10.1021/acs.nanolett.1c04369
ACS Nano. 2021 Dec 27.

One-Step Integration of Tumor Microenvironment-Responsive Calcium and Copper Peroxides Nanocomposite for Enhanced Chemodynamic/Ion-Interference Therapy.

Bin Liu, Yulong Bian, Shuang Liang, Meng Yuan, Shuming Dong, Fei He, Shili Gai, Piaoping Yang, Ziyong Cheng, Jun Lin.

  Recently, various metal peroxide nanomaterials have drawn increasing attention as an efficient hydrogen peroxide (H2O2) self-supplying agent for enhanced tumor therapy. However, a single kind of metal peroxide is insufficient to achieve more effective antitumor performance. Here, a hyaluronic acid modified calcium and copper peroxides nanocomposite has been synthesized by a simple one-step strategy. After effective accumulation at the tumor site due to the enhanced permeability and retention (EPR) effect and specific recognition of hyaluronate acid with CD44 protein on the surface of tumor cells, plenty of Ca2+, Cu2+, and H2O2 can be simultaneously released in acid and hyaluronidase overexpressed tumor microenvironment (TME), generating abundant hydroxyl radical through enhanced Fenton-type reaction between Cu2+ and self-supplying H2O2 with the assistance of glutathione depletion. Overloaded Ca2+ can lead to mitochondria injury and thus enhance the oxidative stress in tumor cells. Moreover, an unbalanced calcium transport channel caused by oxidative stress can further promote tumor calcification and necrosis, which is generally defined as ion-interference therapy. As a result, the synergistic effect of Fenton-like reaction by Cu2+ and mitochondria dysfunction by Ca2+ in ROS generation is performed. Therefore, a TME-responsive calcium and copper peroxides nanocomposite based on one-step integration has been successfully established and exhibits a more satisfactory antitumor efficiency than any single kind of metal peroxide.

Keywords:  calcium peroxide; chemodynamic therapy; copper peroxide; ion-interference therapy; one-step integration

DOI:  https://doi.org/10.1021/acsnano.1c07893
Angew Chem Int Ed Engl. 2021 Dec 28.

DNA Origami-Encoded Integration of Heterostructures.

Xinpei Dai, Xiaoliang Chen, Xinxin Jing, Yinan Zhang, Muchen Pan, Mingqiang Li, Qian Li, Pi Liu, Chunhai Fan, Xiaoguo Liu.

  Integrating dissimilar materials at the nanoscale is crucial for modern electronics and optoelectronics. The structural DNA nanotechnology provides a universal platform for precision assembly of materials; nevertheless, heterogeneous integration of dissimilar materials with DNA nanostructures has yet to be explored. Here we report a DNA origami-encoded strategy for integrating silica-metal heterostructures. Theoretical and experimental studies reveal distinctive mechanisms for the binding and aggregation of silica and metal clusters on protruding double-stranded DNA (dsDNA) strands that are prescribed on the DNA origami template. In particular, the binding energy differences of silica/metal clusters and DNA molecules underlies the accessibilities of dissimilar material areas on DNA origami. We find that, by programming the densities and lengths of protruding dsDNA strands on DNA origami, silica and metal materials can be independently deposited at their predefined areas with a high vertical precision of 2 nm. We demonstrate the integration of silica-gold and silica-silver heterostructures with high site addressability. This DNA nanotechnology-based strategy is thus applicable for integrating various types of dissimilar materials, which opens new routes for bottom-up electronics.

Keywords:  DNA metallization; DNA nanotechnology; DNA origami; DNA silicification

DOI:  https://doi.org/10.1002/anie.202114190
Adv Mater. 2021 Dec 29. e2108479

Rapid Identification of DNA Fragments through Direct Sequencing with Electro-Optical Zero-Mode Waveguides.

Fatemeh Farhangdoust, Feng Cheng, Wentao Liang, Yongmin Liu, Meni Wanunu.

  In contrast to sequence-specific techniques such as polymerase chain reaction (PCR), DNA sequencing does not require prior knowledge of the sample for surveying DNA. However, current sequencing technologies demand high inputs for a suitable library preparation, which typically necessitates DNA amplification, even for single-molecule sequencing methods. Here, we present electro-optical zero-mode waveguides (eZMWs), which can load DNA into the confinement of zero-mode waveguides with high efficiency and negligible DNA fragment length bias. Using eZMWs, we observe highly efficient voltage-induced loading of DNA fragments of various sizes from ultralow inputs (ng-to-pg levels). We demonstrate rapid DNA fragment identification by burst sequencing of short and long DNA molecules (260 bp and 20000 bp) loaded from an equimolar pM-level concentration mixture in just a few-minutes. Our device allows further studies in which low-input DNA capture is essential, for example, in epigenetics, where native DNA is required for obtaining modified base information. This article is protected by copyright. All rights reserved.

Keywords:  Zero-mode waveguides; rapid DNA identification; single-molecule sequencing

DOI:  https://doi.org/10.1002/adma.202108479
J Control Release. 2021 Dec 23. pii: S0168-3659(21)00676-3. [Epub ahead of print]341 812-827

Paclitaxel derivative-based liposomal nanoplatform for potentiated chemo-immunotherapy.

Yingli Wang, Jiang Yu, Dan Li, Liwen Zhao, Bingjun Sun, Jiamei Wang, Zhenjie Wang, Shuang Zhou, Menglin Wang, Yinxian Yang, Hongzhuo Liu, Haotian Zhang, Qingzhi Lv, Qikun Jiang, Zhonggui He, Yongjun Wang.

  The combination of chemotherapy with the immune checkpoint blockade (ICB) therapy is bringing a tremendous hope in the treatment of malignant tumors. However, the treatment efficacy of the existing chemo-immunotherapy is not satisfactory due to the high cost and immunogenicity of ICB antibodies, low response rate to ICB, off-target toxicity of therapeutic agents, and low drug co-delivery efficacy. Therefore, a high-efficient nanosystem combining the delivery of chemotherapeutics with small molecule ICB inhibitors may be promising for an efficient cancer therapy. Herein, a novel reactive oxygen species (ROS)-activated liposome nanoplatform was constructed by the loading of a ROS-sensitive paclitaxel derivative (PSN) into liposomes to overcome the difficulties on delivering paclitaxel mostly represented by premature drug release and a low amount accumulated into the tumor. The innovative liposomal nanosystem was rationally designed by a remote loading of BMS-202 (a small molecule PD-1/PD-L1 inhibitor) and PSN into the liposomes for a ROS-sensitive paclitaxel release and sustained BMS-202 release. The co-loaded liposomes resulted in a high co-loading ability and improved pharmacokinetic properties. An orthotopic 4 T1 breast cancer model was used to evaluate the efficiency of our nanoplatform in vivo, resulting in a superior antitumor activity. The antitumor immunity was activated by paclitaxel-mediated immunogenic cell death, while BMS-202 continuously blocked PD-L1 which could be up-regulated by paclitaxel in tumors to increase the response to ICB and further recover the host immune surveillance. These results revealed that this dual-delivery liposome might provide a promising strategy for a high-efficient chemo-immunotherapy, exhibiting a great potential for clinical translation.

Keywords:  Chemo-immunotherapy; Co-loaded liposomes; Immune checkpoint blockade; Paclitaxel derivative; Remote-loading

DOI:  https://doi.org/10.1016/j.jconrel.2021.12.023
ACS Nano. 2021 Dec 30.

Biomaterial-Mediated Presentation of Jagged-1 Mimetic Ligand Enhances Cellular Activation of Notch Signaling and Bone Regeneration.

Yingrui Deng, Rui Li, Haixing Wang, Boguang Yang, Peng Shi, Yuan Zhang, Qiang Yang, Gang Li, Liming Bian.

  The development from stem cells to adult tissues requires the delicate presentation of numerous crucial inductive cues and the activation of associated signaling pathways. The Notch signaling pathways triggered by ligands such as Jagged-1 have been demonstrated to be essential in various development processes especially in osteogenesis and ossification. However, few studies have capitalized on the osteoinductivity of the Jagged-1 mimetic ligands to enhance the osteogenesis and skeleton regeneration. In this study, we conjugate the porous hyaluronic acid hydrogels with a Jagged-1 mimetic peptide ligand (Jagged-1) and investigate the efficacy of such biomimetic functionalization to promote the mechanotransduction and osteogenesis of human mesenchymal stem cells by activating the Notch signaling pathway. Our findings indicate that the immobilized Jagged-1 mimetic ligand activates Notch signaling via the upregulation of NICD and downstream MSX2, leading to the enhanced mechanotransduction and osteogenesis of stem cells. We further demonstrate that the functionalization of the Jagged-1 ligand in the porous scaffold promotes angiogenesis, regulates macrophage recruitment and polarization, and enhances in situ regeneration of rat calvarial defects. Our findings provide valuable guidance to the design of development-inspired bioactive biomaterials for diverse biomedical applications.

Keywords:  Jagged-1; biomimicking peptides; bone regeneration; hydrogels; osteogenesis

DOI:  https://doi.org/10.1021/acsnano.1c08728
ACS Appl Mater Interfaces. 2021 Dec 27.

Self-Delivery Janus-Prodrug for Precise Immuno-Chemotherapy of Colitis-Associated Colorectal Cancer.

Qixiong Zhang, Shanshan Li, Lan Bai, Dongke Yu, Hui Li, Rongsheng Tong.

  Aromatized thioketal (ATK) linked the immunoregulatory molecule (budesonide, Bud) and the cytotoxic molecule (gemcitabine, Gem) to construct a ROS-activated Janus-prodrug, termed as BAG. Benefiting from the hydrogen bonding, π-π stacking, and other intermolecular interactions, BAG could self-assemble into nanoaggregates (BAG NA) with a well-defined spherical shape and uniform size distribution. Compared to the carrier-based drug delivery system, BAG NA have ultrahigh drug loading content and ROS concentration-dependent drug release. Colitis-associated colorectal cancer (CAC) is a typical disease in which chronic inflammation transforms into tumors. BAG NA can be internalized by colon cancer C26 cells and then triggered by excessive intracellular ROS to release nearly 100% of the drugs. Based on this, BAG NA showed a stronger pro-apoptotic effect than free Bud combined with free Gem. What is gratifying is that orally administered BAG NA can precisely accumulate in the diseased colon tissues of CAC mice induced by AOM/DSS and simultaneously release Bud and Gem. Bud can regulate the tumor immune microenvironment to restore and enhance the cytotoxicity of Gem. Therefore, BAG NA maximizes the synergistic therapeutic effect through co-delivery of Bud and Gem. This work provided a cutting-edge method for constructing self-delivery Janus-prodrug based on ATK and confirmed its potential application in inflammation-related carcinogenesis.

Keywords:  Janus-prodrug; aromatized thioketal; colitis-associated colorectal cancer; self-delivery; synergistic therapy

DOI:  https://doi.org/10.1021/acsami.1c20031
Adv Mater. 2021 Dec 28. e2106516

Nanovesicle-mediated targeted delivery of immune checkpoint blockades to potentiate therapeutic efficacy and prevent side effects.

Mungyo Jung, Mikyung Kang, Byung-Seok Kim, Jihye Hong, Cheesue Kim, Choong-Hyun Koh, Garam Choi, Yeonseok Chung, Byung-Soo Kim.

  Despite the clinically proven efficacies of immune checkpoint blockades, including anti-cytotoxic T lymphocyte-associated protein 4 antibody (αCTLA-4), the low response rate and immune-related adverse events (irAEs) in cancer patients represent major drawbacks of the therapy. These drawbacks of αCTLA-4 therapy are mainly due to the suboptimal activation of tumor-specific cytotoxic T lymphocytes (CTLs) and the systemic non-specific activation of T cells. To overcome such drawbacks, αCTLA-4 was delivered by dendritic cell-derived nanovesicles presenting tumor antigens (DCNV-TAs) that exclusively interact with tumor-specific T cells, leading to selective activation of tumor-specific CTLs. Compared to conventional αCTLA-4 therapy, treatment with αCTLA-4-conjugated DCNV-TAs significantly inhibited tumor growth and reduced irAEs in syngeneic tumor-bearing mice. This study demonstrates that the spatiotemporal presentation of both αCTLA-4 and tumor antigens enables selective activation of tumor-specific T cells and potentiates the antitumor efficacy of αCTLA-4 without inducing systemic irAEs. This article is protected by copyright. All rights reserved.

Keywords:  cancer immunotherapy; dendritic cells; immune checkpoint inhibitors; immune-related adverse events; nanovesicles

DOI:  https://doi.org/10.1002/adma.202106516
ACS Appl Mater Interfaces. 2021 Dec 27.

Peptide-Decorated DNA Nanostructures Promote Site-Specific Hydroxyapatite Growth.

Alexander L Danesi, Dimitra Athanasiadou, Abdulmateen O Aderinto, Prakash Rasie, Leo Y T Chou, Karina M M Carneiro.

  The guiding principle for mineralized tissue formation is that mineral growth occurs through the interaction of Ca2+ and phosphate ions with extracellular matrix (ECM) proteins. Recently, nanoengineered DNA structures have been proposed as mimics to ECM scaffolds. However, these principles have not been applied to mineralized tissues. Here, we describe DNA nanostructures, namely, a DNA nanotube and a DNA origami rectangle that are site specifically functionalized with a mineral-promoting "SSEE" peptide derived from ECM proteins present in mineralized tissues. In the presence of Ca2+ and phosphate ions (mineralizing conditions), site-specific calcium phosphate formation occurred on the DNA nanostructures. Amorphous calcium phosphate or hydroxyapatite was formed depending on the incubation time, shape of the DNA nanostructure, and amount of Ca2+ and phosphate ions present. The ability to design and control the growth of hydroxyapatite through nanoengineered scaffolds provides insights into the mechanisms that may occur during crystal nucleation and growth of mineralized tissues and can inspire mineralized tissue regeneration strategies.

Keywords:  DNA nanotechnology; DNA nanotube; DNA origami; biomineralization; hydroxyapatite; peptide functionalization; site-specific modification

DOI:  https://doi.org/10.1021/acsami.1c19271
Blood. 2021 Dec 27. pii: blood.2021014559. [Epub ahead of print]

Suppression of fibrin(ogen)-driven pathologies through controlled knockdown by lipid nanoparticle delivery of siRNA.

Lih Jiin Juang, Woosuk Steve Hur, Lakmali Munasinghage Silva, Amy W Strilchuk, Brenton Francisco, Jerry Leung, Madelaine K Robertson, Dafna J Groeneveld, Bridget La Prairie, Elizabeth M Chun, Andrew P Cap, James P Luyendyk, Joseph S Palumbo, Pieter R Cullis, Thomas H Bugge, Matthew J Flick, Christian J Kastrup.

Fibrinogen plays a pathologic role in multiple diseases. It contributes to thrombosis and modifies inflammatory and immune responses, supported by studies in mice expressing fibrinogen variants with altered function or with a germline fibrinogen deficiency. However, therapeutic strategies to safely and effectively tailor plasma fibrinogen concentration are lacking. Here, we developed a strategy to tune fibrinogen expression by administering lipid nanoparticle (LNP)-encapsulated siRNA targeting the fibrinogen α chain (siFga). Three distinct LNP-siFga reagents reduced both hepatic Fga mRNA and fibrinogen levels in platelets and plasma, with plasma levels decreased to 42%, 16% and 4% of normal within one-week of administration. Using the most potent siFga, circulating fibrinogen was controllably decreased to 32%, 14%, and 5% of baseline with a 0.5, 1, and 2 mg/kg dose, respectively. Whole blood from mice treated with siFga formed clots with significantly decreased clot strength ex vivo, but siFga treatment did not compromise hemostasis following saphenous vein puncture or tail transection. In an endotoxemia model, siFga suppressed the acute phase response and decreased plasma fibrinogen, D-dimer, and proinflammatory cytokine levels. In a sterile peritonitis model, siFga restored normal macrophage migration in plasminogen-deficient mice. Finally, treatment of mice with siFga decreased the metastatic potential of tumour cells in a manner comparable to that observed in fibrinogen-deficient mice. The results indicate that siFga causes robust and controllable depletion of fibrinogen and provide the proof-of-concept that this strategy can modulate the pleiotropic effects of fibrinogen in relevant disease models.

DOI: https://doi.org/10.1182/blood.2021014559
Adv Healthc Mater. 2021 Dec 30. e2102337

Engineered Cell-Secreted Extracellular Matrix Modulates Cell Spheroid Mechanosensing and Amplifies their Response to Inductive Cues for the Formation of Mineralized Tissues.

T Gonzalez-Fernandez, A J Tenorio, A M Saiz, J K Leach.

  The clinical translation of mesenchymal stromal cell (MSC)-based therapies remains challenging due to rapid cell death and poor control over cell behavior. Compared to monodisperse cells, the aggregation of MSCs into spheroids increases their tissue-forming potential by promoting cell-cell interactions. However, MSCs initially lack engagement with an endogenous extracellular matrix (ECM) when formed into spheroids. We previously demonstrated the instructive nature of an engineered, cell-secreted ECM to promote survival and differentiation of adherent MSCs. Herein, we hypothesized that the incorporation of this cell-secreted ECM during spheroid aggregation would enhance MSC osteogenic potential by promoting cell-matrix and cell-cell interactions. ECM-loaded spheroids contained higher collagen and glycosaminoglycan content, and MSCs exhibited increased mechanosensitivity to ECM through YAP activation via integrin α2β1 binding. ECM-loaded spheroids sustained greater MSC viability and proliferation and were more responsive to soluble cues for lineage-specific differentiation than spheroids without ECM or loaded with collagen. The encapsulation of ECM-loaded spheroids in instructive alginate gels resulted in spheroid fusion and enhanced osteogenic differentiation. These results highlight the clinical potential of ECM-loaded spheroids as building blocks for the repair of musculoskeletal tissues. This article is protected by copyright. All rights reserved.

Keywords:  Extracellular matrix; mesenchymal stromal cells; spheroids

DOI:  https://doi.org/10.1002/adhm.202102337
Adv Mater. 2021 Dec 28. e2108232

Highly Transparent and Self-Healable Solar Thermal Anti-/De-Icing Surfaces: When Ultrathin MXene Multilayers Marry Solid Slippery Self-Cleaning Coating.

Wenwen Niu, George Y Chen, Haolan Xu, Xiaokong Liu, Junqi Sun.

  Solar anti-/de-icing can solve icing problems by converting sunlight into heat. One of the biggest problems, which has long been plaguing the design of solar anti-/de-icing surfaces, is that photothermal materials are always lightproof and appear black, because of the mutual exclusiveness between generating heat and retaining transparency. Herein, we report a highly transparent and scalable solar anti-/de-icing surface, which enables the coated glass to exhibit high transparency (>77% transmittance at 550 nm) and meanwhile, causes a >30°C surface temperature increase relative to ambient under 1.0 sun illumination. Such a transparent anti-/de-icing surface can be fabricated onto a large class of substrates (e.g., glass, ceramics, metals, plastics), by applying a solid omniphobic slippery coating onto layer-by-layer assembled ultrathin MXene multilayers. Hence, the surface possesses self-cleaning ability to shed waterborne and oil-based liquids thanks to residue-free slipping motion. Passive anti-icing and active de-icing capabilities are, respectively, obtained on the solar thermal surface, which effectively prevents water from freezing and simultaneously melts pre-formed ice and thick frost. The self-cleaning effect enables residue-free removal of unfrozen water and interfacially melted ice/frost to boost the anti-/de-icing efficiency. Importantly, the surface is capable of self-healing under illumination to repair physical damage and chemical degradation. This article is protected by copyright. All rights reserved.

Keywords:  anti-/de-icing; coatings; layer-by-layer assembly; photothermal materials; self-healing materials

DOI:  https://doi.org/10.1002/adma.202108232
Angew Chem Int Ed Engl. 2021 Dec 29.

Semiconducting Polymer Nano-regulators with Cascading Activation for Photodynamic Cancer Immunotherapy.

Shasha He, Jing Liu, Chi Zhang, Jun Wang, Kanyi Pu.

  Combination photoimmunotherapy holds promise for tumor suppression; however, smart phototherapeutic agents that only activate their immunotherapeutic action in tumor have been rarely developed, which have the potential advantage of reduced side effect. Herein, we report a semiconducting polymer nano-regulator (SPN T ) with cascading activation for combinational photodynamic immunotherapy of cancer. SPN T comprises an immunoregulator (M-Trp: 1-methyltryptophan ) conjugating to the side chain of semiconducting polymer backbone using an apoptotic biomarker-cleavable linker. Under near-infrared (NIR) laser irradiation, SPN T produces singlet oxygen ( 1 O 2 ) to cause immunogenic apoptosis . Concurrently, the upregulation of apoptotic biomarker triggers the specific cleavage of M-Trp from SPN T , leading to specific intratumoral immunotherapeutic activation. Released M-Trp inhibits indoleamine 2,3-dioxygenase (IDO) activity, and thus decreases regulatory T cells (Tregs) formation and drives cytotoxic T lymphocytes (CTLs) infiltration. SPN T -mediated combination photodynamic immunotherapy thus reprograms the tumor immune microenvironment (TIME), resulting in efficient suppression of both primary and distant tumors, and inhibition of lung metastasis.

Keywords:  cancer therapy; immunotherapy; nanomedicine; photodynamic therapy

DOI:  https://doi.org/10.1002/anie.202116669
Methods Mol Biol. 2022 ;2445 171-182

Concepts and Design of Introducing Synthetic MicroRNAs into Mammalian Cells.

Per Hydbring.

  MicroRNAs are pleiotropic gene modulators affecting numerous cellular processes in development and disease. Due to their small size, microRNAs can easily be synthesized for the purpose of mechanistic or therapeutic studies in biological processes, including autophagy. Depending on the biological question posed, approaches of modulating microRNAs involve either microRNA mimic or inhibitory nucleic acid molecules. This protocol outlines the detailed methodological steps to introduce synthetic microRNA drugs into target cells in vitro and in vivo and how to monitor their function. In addition, it provides insights on how to control the adverse effects when ectopically expressing synthetic microRNA mimic molecules.

Keywords:  Autophagy; MicroRNA; Nanoparticles; Stem-loop RT-qPCR; Transfection

DOI:  https://doi.org/10.1007/978-1-0716-2071-7_11
Adv Mater. 2021 Dec 26. e2106941

Supramolecular Reinforcement of Polymer-Nanoparticle Hydrogels for Modular Materials Design.

Giovanni Bovone, Elia A Guzzi, Stéphane Bernhard, Tim Weber, Dalia Dranseikiene, Mark W Tibbitt.

  Moldable hydrogels are increasingly used as injectable or extrudable materials in biomedical and industrial applications owing to their ability to flow under applied stress (shear-thin) and reform a stable network (self-heal). Nanoscale components can be added to dynamic polymer networks to modify their mechanical properties and broaden the scope of applications. Viscoelastic polymer-nanoparticle (PNP) hydrogels comprise a versatile and tunable class of dynamic nanocomposite materials that form via reversible interactions between polymer chains and nanoparticles. However, PNP hydrogel formation is restricted to specific interactions between select polymers and nanoparticles, resulting in a limited range of mechanical properties and constraining their utility. Here, we introduce a facile strategy to reinforce PNP hydrogels through the simple addition of α-cyclodextrin (αCD) to the formulation. The formation of polypseudorotoxanes between αCD and the hydrogel components resulted in a drastic enhancement of the mechanical properties. Furthermore, supramolecular reinforcement of CD-PNP hydrogels enabled us to decouple mechanical properties and material functionality. This allowed for modular exchange of structural components from a library of functional polymers and nanoparticles. We leveraged αCD supramolecular binding motifs to form CD-PNP hydrogels with biopolymers for high fidelity 3D (bio)printing and drug delivery as well as with inorganic NPs to engineer magnetic or conductive materials. This article is protected by copyright. All rights reserved.

Keywords:  3D printing; advanced composites; dynamic polymer networks; nanocomposite hydrogels; supramolecular materials

DOI:  https://doi.org/10.1002/adma.202106941
Acta Biomater. 2021 Dec 22. pii: S1742-7061(21)00824-2. [Epub ahead of print]

Engineering a Photosynthetic Bacteria-incorporated Hydrogel for Infected Wound Healing.

Erman Zhao, Huifang Liu, Yaru Jia, Tingshan Xiao, Jiaxin Li, Guoqiang Zhou, June Wang, Xiaohan Zhou, Xing-Jie Liang, Jinchao Zhang, Zhenhua Li.

  Treating wounds with multidrug-resistant bacterial infections remains a huge and arduous challenge. In this work, we prepared a "live-drug"-encapsulated hydrogel dressing for the treatment of multidrug-resistant bacterial infections and full-thickness skin incision repair. Our live dressing was comprised of photosynthetic bacteria (PSB) and extracellular matrix (ECM) gel with photothermal, antibacterial and antioxidant properties, as well as good cytocompatibility and blood compatibility. More interestingly, live PSB could be regarded as not only photothermal agents but also as anti-inflammatory agents to promote wound healing owing to their antioxidant metabolites. In vitro and in vivo studies showed that the PSB hydrogel not only had a high killing rate against methicillin-resistant Staphylococcus aureus (MRSA) but it also accelerated collagen deposition and granulation tissue formation by promoting cell proliferation and migration, which significantly promoted skin tissue regeneration and wound healing. We believe that the large-scale production of PSB Gel-based therapeutic dressings has the advantages of easy use and promising clinical applications. STATEMENT OF SIGNIFICANCE: Rapid wound healing and the treatment of bacterial infections have always been the two biggest challenges in the field of wound care. We prepared a "live drug" dressing by encapsulating photosynthetic bacteria into an extracellular matrix hydrogel to sterilize the wound and promote wound healing. First, photosynthetic bacteria are not only a photothermal agent for photothermal wound sterilization, but also possess the anti-inflammatory capacity to enhance wound healing due to their antioxidant metabolites. Second, the extracellular matrix hydrogel is rich in a variety of growth factors and nutrients to promote cell migration and accelerate wound healing. Third, photosynthetic bacteria are not only green and non-toxic, but also can be obtained on a large scale, which facilitates manufacturing and clinical transformation.

Keywords:  Antibacterial; Antioxidant metabolites; Extracellular matrix hydrogel; Photosynthetic bacteria; Wound healing

DOI:  https://doi.org/10.1016/j.actbio.2021.12.017
Adv Healthc Mater. 2021 Dec 31. e2101678

Mimicking Native Heart Tissue Physiology and Pathology in Silk Fibroin Constructs Through Perfusion-based Dynamic Mechanical Stimulation Microdevice.

Shreya Mehrotra, Bruna Alice Gomes de Melo, Mario Miscuglio, Kiavash Kiaee, Su Ryon Shin, Biman Behari Mandal.

  In vitro cardiomyocyte maturation is an imperative step to replicate native heart tissue-like structures as cardiac tissue grafts or as drug screening platforms. Cardiomyocytes are known to interpret biophysical cues such as stiffness, topography, external mechanical stimulation or dynamic perfusion load through mechanotransduction and change their behaviour, organization and maturation. In this regard, we have tried to deliver a silk-based cardiac tissue coupled with a dynamic perfusion-based mechanical stimulation platform (DMM) for achieving maturation and functionality in vitro. Silk fibroin was used to fabricate lamellar scaffolds to provide native tissue-like anisotropic architecture and were found to be non-immunogenic and biocompatible allowing cardiomyocyte attachment and growth in vitro. Further, the scaffolds displayed excellent mechanical properties by their ability to undergo cyclic compressions without any deformation when placed in the DMM. Gradient compression strains (5% to 20%), mimicking the native physiological and pathological conditions, were applied to the cardiomyocyte culture seeded on lamellar silk scaffolds in the DMM. A strain-dependent difference in cardiomyocyte maturation, gene expression, sarcomere elongation, and ECM formation was observed. These silk-based cardiac tissues matured in the DMM could open up several avenues towards the development of host-specific grafts and in vitro models for drug screening. This article is protected by copyright. All rights reserved.

Keywords:  Silk; cardiac tissue engineering; cardiomyocyte; compression; lamellar scaffolds; mechanotransduction

DOI:  https://doi.org/10.1002/adhm.202101678
Adv Mater. 2021 Dec 29. e2108908

Reshaping Tumor Immune Microenvironment Based on Light Activated Nano-Platform for Efficient Cancer Therapy.

Zebin Yang, Yu Luo, Huizhu Yu, Kaicheng Liang, Miao Wang, Qigang Wang, Bo Yin, Hangrong Chen.

  Immunosuppressive tumor microenvironment (TME) always cause poor antitumor immune efficacy, prone to relapse and metastasis. Herein, a novel polyvinyl pyrrolidone (PVP) modified BiFeO3 /Bi2 WO6 (BFO/BWO) with p-n type heterojunction was constructed for reshaping immunosuppressive TME. Reactive oxygen species could be generated under light activation by the well separation of hole (h+ )-electron (e- ) pairs owing to the heterojunction in BFO/BWO-PVP NPs. Interestingly, the h+ can trigger the decomposition of H2 O2 to generate O2 for alleviating tumor hypoxia, which not only sensitizes photodynamic therapy (PDT) and radiotherapy (RT), but also promotes the tumor-associated macrophages (TAMs) polarization from M2 to M1 phenotype, beneficial to decrease the expression of HIF-1α. Importantly, such a light activated nano-platform combing with RT could efficiently activate and recruit cytotoxic T lymphocytes to infiltrate in tumor tissues, as well as stimulate TAMs to M1 phenotype, dramatically reverse the immunosuppressive TME into the immunoactive one and further boost immune memory responses. Moreover, BFO/BWO-PVP NPs also present high performance of computed tomography imaging contrast. Taken together, this work offers a novel paradigm for achieving O2 self-supplement of inorganic nano-agent and reshaping tumor immune microenvironment to effective inhibition of cancer as well as metastasis and recurrence. This article is protected by copyright. All rights reserved.

Keywords:  hypoxia; metastasis; photodynamic therapy; recurrence; tumor immune microenvironment

DOI:  https://doi.org/10.1002/adma.202108908