bims-drudre 2022-05-15 papers

bims-drudre

Biomed News

on Targeted drug delivery and programmed release mechanisms

Issue of 2022–05–15
27 papers selected by
Ceren Kimna, Technical University of Munich

In vivo hitchhiking of immune cells by intracellular self-assembly of bacteria-mimetic nanomedicine for targeted therapy of melanoma.
The upregulated intestinal folate transporters direct the uptake of ligand-modified nanoparticles for enhanced oral insulin delivery.
Self-assembled polysaccharide nanogel delivery system for overcoming tumor immune resistance.
Enhancing CRISPR/Cas gene editing through modulating cellular mechanical properties for cancer therapy.
Targeted neutrophil-mimetic liposomes promote cardiac repair by adsorbing proinflammatory cytokines and regulating the immune microenvironment.
A Lysosome-Targeting Self-Condensation Prodrug-Nanoplatform System for Addressing Drug Resistance of Cancer.
Tumor-Microenvironment-Activated NIR-II Nanotheranostic Platform for Precise Diagnosis and Treatment of Colon Cancer.
Polymer Nanoparticles Overcome Drug Resistance by a Dual-Targeting Apoptotic Signaling Pathway in Breast Cancer.
Masking the immunotoxicity of interleukin-12 by fusing it with a domain of its receptor via a tumour-protease-cleavable linker.
Role of polyplex charge density in lipopolyplexes.
Penetrating-peptide-mediated non-invasive Axitinib delivery for anti-neovascularisation.
Recent advances in delivering RNA-based therapeutics to mitochondria.
One-Component DNA Mechanoprobes for Facile Mechanosensing in Photopolymerized Hydrogels and Elastomers.
Cationic Bottlebrush Polymers Outperform Linear Polycation Analogues for pDNA Delivery and Gene Expression.
A sustainable single-component "Silk nacre".
Nanosized Janus AuNR-Pt Motor for Enhancing NIR-II Photoacoustic Imaging of Deep Tumor and Pt2+ Ion-Based Chemotherapy.
An Injectable Peptide Hydrogel Constructed of Natural Antimicrobial Peptide J-1 and ADP Shows Anti-Infection, Hemostasis, and Antiadhesion Efficacy.
Dual antimicrobial-loaded biodegradable nanoemulsions for synergistic treatment of wound biofilms.
Infant Skin Friendly Adhesive Hydrogel Patch Activated at Body Temperature for Bioelectronics Securing and Diabetic Wound Healing.
Shape Designed Implanted Drug Delivery System for In Situ Hepatocellular Carcinoma Therapy.
A Simple and Efficient Strategy for Preparing a Cell-Spheroid-Based Bioink.
Multilayered Ordered Protein Arrays Self-Assembled from a Mixed Population of Virus-like Particles.
PERSIST platform provides programmable RNA regulation using CRISPR endoRNases.
Fully implantable wireless batteryless vascular electronics with printed soft sensors for multiplex sensing of hemodynamics.
Self-Assembly of Poly(Janus particle)s into Unimolecular and Oligomeric Spherical Micelles.
Tailored modular assembly derived self-healing polythioureas with largely tunable properties covering plastics, elastomers and fibers.
Intelligent and robust DNA robots capable of swarming into leakless nonlinear amplification in response to a trigger.

Sci Adv. 2022 May 13. 8(19): eabn1805

In vivo hitchhiking of immune cells by intracellular self-assembly of bacteria-mimetic nanomedicine for targeted therapy of melanoma.

Cheng Gao, Qingfu Wang, Junyan Li, Cheryl H T Kwong, Jianwen Wei, Beibei Xie, Siyu Lu, Simon M Y Lee, Ruibing Wang.

Cell-based drug carriers are mostly prepared in vitro, which may negatively affect the physiological functions of cells, and induce possible immune rejections when applied to different individuals. In addition, the immunosuppressive tumor microenvironment limits immune cell-mediated delivery. Here, we report an in vivo strategy to construct cell-based nanomedicine carriers, where bacteria-mimetic gold nanoparticles (GNPs) are intravenously injected, selectively phagocytosed by phagocytic immune cells, and subsequently self-assemble into sizable intracellular aggregates via host-guest interactions. The intracellular aggregates minimize exocytosis of GNPs from immune cells and activate the photothermal property via plasmonic coupling effects. Phagocytic immune cells carry the intracellular GNP aggregates to melanoma tissue via inflammatory tropism. Moreover, an initial photothermal treatment (PTT) of the tumor induces tumor damage that subsequently provides positive feedback to recruit more immune cell-based carriers for enhanced targeting efficiency. The optimized secondary PTT notably improves antitumor immunotherapy, further strengthened by immune checkpoint blockade.

DOI: https://doi.org/10.1126/sciadv.abn1805
Acta Pharm Sin B. 2022 Mar;12(3): 1460-1472

The upregulated intestinal folate transporters direct the uptake of ligand-modified nanoparticles for enhanced oral insulin delivery.

Jingyi Li, Yaqi Zhang, Miaorong Yu, Aohua Wang, Yu Qiu, Weiwei Fan, Lars Hovgaard, Mingshi Yang, Yiming Li, Rui Wang, Xiuying Li, Yong Gan.

  Transporters are traditionally considered to transport small molecules rather than large-sized nanoparticles due to their small pores. In this study, we demonstrate that the upregulated intestinal transporter (PCFT), which reaches a maximum of 12.3-fold expression in the intestinal epithelial cells of diabetic rats, mediates the uptake of the folic acid-grafted nanoparticles (FNP). Specifically, the upregulated PCFT could exert its function to mediate the endocytosis of FNP and efficiently stimulate the traverse of FNP across enterocytes by the lysosome-evading pathway, Golgi-targeting pathway and basolateral exocytosis, featuring a high oral insulin bioavailability of 14.4% in the diabetic rats. Conversely, in cells with relatively low PCFT expression, the positive surface charge contributes to the cellular uptake of FNP, and FNP are mainly degraded in the lysosomes. Overall, we emphasize that the upregulated intestinal transporters could direct the uptake of ligand-modified nanoparticles by mediating the endocytosis and intracellular trafficking of ligand-modified nanoparticles via the transporter-mediated pathway. This study may also theoretically provide insightful guidelines for the rational design of transporter-targeted nanoparticles to achieve efficient drug delivery in diverse diseases.

Keywords:  Diabetes; Endocytosis; Expression level; Intracellular trafficking; Ligand-modified nanoparticles; Oral insulin delivery; Proton-coupled folate transporter; Transporter

DOI:  https://doi.org/10.1016/j.apsb.2021.07.024
J Control Release. 2022 May 05. pii: S0168-3659(22)00257-7. [Epub ahead of print]

Self-assembled polysaccharide nanogel delivery system for overcoming tumor immune resistance.

Daisuke Muraoka, Naozumi Harada, Hiroshi Shiku, Kazunari Akiyoshi.

  In therapeutic cancer vaccines, vaccine antigens must be efficiently delivered to the antigen-presenting cells (dendritic cells and macrophages) located in the lymphoid organs (lymph nodes and spleen) at the appropriate time to induce a potent antitumor immune response. Nanoparticle-based delivery systems in cancer immunotherapy are of great interest in recent year. We have developed a novel cancer vaccine that can use self-assembled polysaccharide nanogel of cholesteryl group-modified pullulan (CHP) as an antigen delivery system for clinical cancer immunotherapy for the first time. Additionally, we recently proposed a novel technology that uses CHP nanogels to regulate the function of tumor-associated macrophages, leading to an improvement in the tumor microenvironment. When combined with other immunotherapies, macrophage function modulation using CHP nanogels demonstrated a potent inhibitory effect against cancers resistant to immune checkpoint inhibition therapies. In this review, we discuss the applications of our unique drug nanodelivery system for CHP nanogels.

Keywords:  Cancer vaccine; Lymph node delivery; Nanogel; Tumor immune resistance; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.jconrel.2022.05.004
Nat Nanotechnol. 2022 May 12.

Enhancing CRISPR/Cas gene editing through modulating cellular mechanical properties for cancer therapy.

Di Zhang, Guoxun Wang, Xueliang Yu, Tuo Wei, Lukas Farbiak, Lindsay T Johnson, Alan Mark Taylor, Jiazhu Xu, Yi Hong, Hao Zhu, Daniel J Siegwart.

Genome editing holds great potential for cancer treatment due to the ability to precisely inactivate or repair cancer-related genes. However, delivery of CRISPR/Cas to solid tumours for efficient cancer therapy remains challenging. Here we targeted tumour tissue mechanics via a multiplexed dendrimer lipid nanoparticle (LNP) approach involving co-delivery of focal adhesion kinase (FAK) siRNA, Cas9 mRNA and sgRNA (siFAK + CRISPR-LNPs) to enable tumour delivery and enhance gene-editing efficacy. We show that gene editing was enhanced >10-fold in tumour spheroids due to increased cellular uptake and tumour penetration of nanoparticles mediated by FAK-knockdown. siFAK + CRISPR-PD-L1-LNPs reduced extracellular matrix stiffness and efficiently disrupted PD-L1 expression by CRISPR/Cas gene editing, which significantly inhibited tumour growth and metastasis in four mouse models of cancer. Overall, we provide evidence that modulating the stiffness of tumour tissue can enhance gene editing in tumours, which offers a new strategy for synergistic LNPs and other nanoparticle systems to treat cancer using gene editing.

DOI: https://doi.org/10.1038/s41565-022-01122-3
J Nanobiotechnology. 2022 May 07. 20(1): 218

Targeted neutrophil-mimetic liposomes promote cardiac repair by adsorbing proinflammatory cytokines and regulating the immune microenvironment.

Jing Chen, Yanan Song, Qiaozi Wang, Qiyu Li, Haipeng Tan, Jinfeng Gao, Ning Zhang, Xueyi Weng, Dili Sun, Wusiman Yakufu, Zhengmin Wang, Juying Qian, Zhiqing Pang, Zheyong Huang, Junbo Ge.

  Acute myocardial infarction (MI) induces a sterile inflammatory response that may result in poor cardiac remodeling and dysfunction. Despite the progress in anti-cytokine biologics, anti-inflammation therapy of MI remains unsatisfactory, due largely to the lack of targeting and the complexity of cytokine interactions. Based on the nature of inflammatory chemotaxis and the cytokine-binding properties of neutrophils, we fabricated biomimetic nanoparticles for targeted and broad-spectrum anti-inflammation therapy of MI. By fusing neutrophil membranes with conventional liposomes, we fabricated biomimetic liposomes (Neu-LPs) that inherited the surface antigens of the source cells, making them ideal decoys of neutrophil-targeted biological molecules. Based on their abundant chemokine and cytokine membrane receptors, Neu-LPs targeted infarcted hearts, neutralized proinflammatory cytokines, and thus suppressed intense inflammation and regulated the immune microenvironment. Consequently, Neu-LPs showed significant therapeutic efficacy by providing cardiac protection and promoting angiogenesis in a mouse model of myocardial ischemia-reperfusion. Therefore, Neu-LPs have high clinical translation potential and could be developed as an anti-inflammatory agent to remove broad-spectrum inflammatory cytokines during MI and other neutrophil-involved diseases.

Keywords:  Inflammation neutralization; Myocardial ischemia–reperfusion injury; Neutrophil biomimetic; Targeted delivery

DOI:  https://doi.org/10.1186/s12951-022-01433-6
Nano Lett. 2022 May 12.

A Lysosome-Targeting Self-Condensation Prodrug-Nanoplatform System for Addressing Drug Resistance of Cancer.

Da-Yong Hou, Man-Di Wang, Ni-Yuan Zhang, Shaoxin Xu, Zhi-Jia Wang, Xing-Jie Hu, Gan-Tian Lv, Jia-Qi Wang, Mei-Yu Lv, Li Yi, Lu Wang, Dong-Bing Cheng, Taolei Sun, Hao Wang, Wanhai Xu.

  Lysosome-targeting self-assembling prodrugs had emerged as an attractive approach to overcome the acquisition of resistance to chemotherapeutics by inhibiting lysosomal sequestration. Taking advantage of lysosomal acidification induced intracellular hydrolytic condensation, we developed a lysosomal-targeting self-condensation prodrug-nanoplatform (LTSPN) system for overcoming lysosome-mediated drug resistance. Briefly, the designed hydroxycamptothecine (HCPT)-silane conjugates self-assembled into silane-based nanoparticles, which were taken up into lysosomes by tumor cells. Subsequently, the integrity of the lysosomal membrane was destructed because of the acid-triggered release of alcohol, wherein the nanoparticles self-condensed into silicon particles outside the lysosome through intracellular hydrolytic condensation. Significantly, the LTSPN system reduced the half-maximal inhibitory concentration (IC50) of HCPT by approximately 4 times. Furthermore, the LTSPN system realized improved control of large established tumors and reduced regrowth of residual tumors in several drug-resistant tumor models. Our findings suggested that target destructing the integrity of the lysosomal membrane may improve the therapeutic effects of chemotherapeutics, providing a potent treatment strategy for malignancies.

Keywords:  Bladder cancer; Drug resistance; Prodrug; Self-assembly; Self-condensation

DOI:  https://doi.org/10.1021/acs.nanolett.2c00540
ACS Appl Mater Interfaces. 2022 May 13.

Tumor-Microenvironment-Activated NIR-II Nanotheranostic Platform for Precise Diagnosis and Treatment of Colon Cancer.

Renbin Zhou, Tymish Y Ohulchanskyy, Yunjian Xu, Roman Ziniuk, Hao Xu, Liwei Liu, Junle Qu.

  Rational design of tumor-microenvironment (TME)-activated nanoformulation for precisely targeted cancer treatment has recently attracted an enormous attention. However, the all-in-one TME-activated theranostic nanosystems with a simple preparation and high biocompatibility are still rarely reported. Herein, catalase nanocrystals (CatCry) are first introduced as a tumor microenvironment activatable nanoplatform for selective theranostics of colon cancer. They are engaged as (i) a "nanoreactor" for silver nanoparticles (AgNP) synthesis, (ii) a nanovehicle for tumor delivery of anticancer drug doxorubicin (DOX), and (iii) an in situ O2 generator to relief tumor hypoxia. When CatCry-AgNP-DOX nanoformulation is within a tumor, the intratumoral H2S turns AgNP into Ag2S nanoparticles, inducing a photothermal effect and NIR-II emission under 808 nm laser irradiation and also triggering DOX release. Simultaneously, CatCry catalyzes intratumoral H2O2 into O2, relieving hypoxia and enhancing chemotherapy. In contrast, when delivered to healthy tissue without increased concentration of H2S, the developed nanoformulation remains in the "off" state and no theranostic action takes place. Studies with colon cancer cells in vitro and a murine colon cancer model in vivo demonstrated that CatCry-AgNP-DOX delivered a synergistic combination of PTT and enhanced chemotherapy, enabling complete eradication of tumor with minimal side effects. This work not only introduces nanoplatform for theranostics of H2S-rich tumors but also suggests a general strategy for protein-crystal-based nanomedicine.

Keywords:  H2S activatable; NIR-II imaging; cancer chemotherapy; photothermal therapy; protein nanocrystals

DOI:  https://doi.org/10.1021/acsami.2c04242
ACS Appl Mater Interfaces. 2022 May 11.

Polymer Nanoparticles Overcome Drug Resistance by a Dual-Targeting Apoptotic Signaling Pathway in Breast Cancer.

Ning Li, Dong Gao, Chen Li, Baiqi Wang, Boying Li, Benkai Bao, Manman Wu, Mengying Li, Chengfen Xing.

  Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) activating therapy has received wide attention due to its capacity to precisely induce cancer cell apoptosis. However, drug resistance and the poor pharmacokinetic properties of TRAIL protein are obstacles in TRAIL-based therapy for cancer. Herein, a strategy is developed to remotely control and specifically initiate TRAIL-mediated apoptotic signaling to promote TRAIL-resistant cancer cell apoptosis using near-infrared (NIR) light-absorbing conjugated polymer nanoparticles (CPNs). Upon 808 nm laser excitation, the promoter 70 kilodalton heat shock protein (HSP70) initiates transcription of the TRAIL gene in response to heat shock, thereby expressing TRAIL protein in breast cancer cells, which activates the TRAIL-mediated apoptosis signaling pathway. Simultaneously, the CPNs locally release W-7, which targets calmodulin (CaM) and further promotes caspase-8 cleavage and enhances cancer cell apoptosis. Both in vitro and in vivo results demonstrate that CPNs/W-7/pTRAIL produces an excellent synergistic therapeutic effect on breast cancer upon near-infrared light with low toxicity. Therefore, this work provides a strategy for overcoming drug resistance through dual-targeting TRAIL-mediated apoptotic signaling in breast cancer.

Keywords:  TRAIL; conjugated polymer nanoparticles; drug resistance; dual-targeting; near-infrared light

DOI:  https://doi.org/10.1021/acsami.1c23146
Nat Biomed Eng. 2022 May 09.

Masking the immunotoxicity of interleukin-12 by fusing it with a domain of its receptor via a tumour-protease-cleavable linker.

Aslan Mansurov, Peyman Hosseinchi, Kevin Chang, Abigail L Lauterbach, Laura T Gray, Aaron T Alpar, Erica Budina, Anna J Slezak, Seounghun Kang, Shijie Cao, Ani Solanki, Suzana Gomes, John-Michael Williford, Melody A Swartz, Juan L Mendoza, Jun Ishihara, Jeffrey A Hubbell.

Immune-checkpoint inhibitors have shown modest efficacy against immunologically 'cold' tumours. Interleukin-12 (IL-12)-a cytokine that promotes the recruitment of immune cells into tumours as well as immune cell activation, also in cold tumours-can cause severe immune-related adverse events in patients. Here, by exploiting the preferential overexpression of proteases in tumours, we show that fusing a domain of the IL-12 receptor to IL-12 via a linker cleavable by tumour-associated proteases largely restricts the pro-inflammatory effects of IL-12 to tumour sites. In mouse models of subcutaneous adenocarcinoma and orthotopic melanoma, masked IL-12 delivered intravenously did not cause systemic IL-12 signalling and eliminated systemic immune-related adverse events, led to potent therapeutic effects via the remodelling of the immune-suppressive microenvironment, and rendered cold tumours responsive to immune-checkpoint inhibition. We also show that masked IL-12 is activated in tumour lysates from patients. Protease-sensitive masking of potent yet toxic cytokines may facilitate their clinical translation.

DOI: https://doi.org/10.1038/s41551-022-00888-0
Nanoscale. 2022 May 10.

Role of polyplex charge density in lipopolyplexes.

Jianxiang Huang, Wei Song, Lijun Meng, Youqing Shen, Ruhong Zhou.

Lipopolyplexes have received extensive attention lately in gene therapy delivery. However, the interactions between the polyplex and the liposome and their underlying molecular mechanisms remain to be elucidated. Here, we adopted a simple model, mainly to illustrate the impact of polyplex charge density on the self-assembly of liposomes (containing DOPE and CHEMS lipids) using coarse-grained molecular dynamics simulations. Our simulation results show that when the charge density increases in the polyplex, more lipids, especially CHEMS (a negatively charged helper lipid) lipids, are attracted to the polyplex (positively charged) surface, and meanwhile nearby water molecules are driven away from the polyplex, resulting in a less spherical liposome. Energy decomposition analyses further reveal that, at higher charge densities, the polyplex exhibits much stronger interactions with CHEMS lipids than with water molecules, with the majority contribution from electrostatic interactions. In addition, the mobility of lipids, especially CHEMS, is reduced as the polyplex charge density increases, indicating a more rigid liposome. Overall, our molecular dynamics simulations elucidate the influence of polyplex charge density on the liposome self-assembly process at the atomic level, which provides a complementary approach to experiments for a better understanding of this promising gene therapy delivery system.

DOI: https://doi.org/10.1039/d1nr07897f
J Control Release. 2022 May 07. pii: S0168-3659(22)00263-2. [Epub ahead of print]

Penetrating-peptide-mediated non-invasive Axitinib delivery for anti-neovascularisation.

Yuehong Huang, Yutuo Zhu, Danyang Cai, Qi Guo, Jiaqing Wang, Lei Lei, Xingyi Li, Shuai Shi.

  The unique physiological makeup of the eye limits the use of small-molecule drugs for treating the posterior segment of the eye. Nevertheless, transmembrane-peptide-mediated non-invasive drug delivery can serve as an ideal treatment strategy, as it is capable of delivering small-molecule drugs across the membrane in the form of eye drops, thereby achieving the effective treatment of neovascularisation in the posterior cavity. In this study, we screened and compared the posterior segment distribution of two poly(ethylene glycol)-distearoylphosphatidylethanolamine carriers modified using targeting-peptides. Thereafter, a transmembrane peptide (i.e., PENE) with a greater ability of transmembrane delivery was selected for delivering the anti-vascular drug (i.e., Axitinib) to the posterior segment of the eye. Using two different mouse models with fundus neovascular diseases, the complete non-invasive delivery of Axitinib to the posterior segment of the eye was confirmed using the targeted system; the designed eye drops (i.e., PENE-nanoparticles) could achieve drug distribution to the retina and veins of the eye as well as good drug permeability for renewal. Moreover, using the eye-drop treatment, neovascularisation was substantially reduced, demonstrating the high efficacy of this drug delivery system. This study, which combines nanodrug-loading technology and the transmembrane delivery of penetrating-peptides to achieve the goal of the non-invasive delivery of small-molecule drugs through the dense blood vessels of the sclera, shows wide applicability and considerably expands the use of ocular drugs. Thus, this study is expected to help develop a more acceptable drug administration strategy for the drug treatment of the posterior segment of the eye.

Keywords:  Anti-neovascularization; Nanoparticles; Non-invasive delivery; Penetrating-peptides; Posterior eye diseases

DOI:  https://doi.org/10.1016/j.jconrel.2022.05.009
Expert Opin Biol Ther. 2022 May 11. 1-11

Recent advances in delivering RNA-based therapeutics to mitochondria.

Yuma Yamada, Sen Ishizuka, Manae Arai, Minako Maruyama, Hideyoshi Harashima.

   INTRODUCTION: After the emergence of lipid nanoparticles (LNP) containing therapeutic mRNA as vaccines for use against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the clinical usefulness of nucleic acid-encapsulated LNPs is now a fact. In addition to the nucleus and cytoplasm, mitochondria, which have their own genome, are a site where nucleic acids function in the cell. Gene therapies targeting mitochondria are expected to pave the way for the next generation of therapies.
AREAS COVERED: Methods for delivering nucleic acids to mitochondria are needed in order to realize such innovative therapies. However, only a few reports on delivery systems targeting mitochondria have appeared. In this review, we summarize the current state of research on RNA-based therapeutics targeted to mitochondria, with emphasis on mitochondrial RNA delivery therapies and on therapies that involve the use of mitochondrial genome editing devices.
EXPERT OPINION: We hope that this review article will focus our attention to this area of research, stimulate more interest in this field of research, and lead to the development of mitochondria-targeted nucleic acid medicine. It has the potential to become a major weapon against urgent and unknown diseases, including SARS-CoV-2 infections.

Keywords:  MITO-Porter; Mitochondria; RNA delivery therapy; drug delivery system; gene editing; gene therapy

DOI:  https://doi.org/10.1080/14712598.2022.2070427
ACS Macro Lett. 2021 Jun 15. 10(6): 671-678

One-Component DNA Mechanoprobes for Facile Mechanosensing in Photopolymerized Hydrogels and Elastomers.

Guido Creusen, Ricarda Sophia Schmidt, Andreas Walther.

DNA mechanosensors offer unique properties for mechano-adaptive and self-reporting materials, such as programmable bond strength and geometrical strain response, tunable fluorescent strain sensing, interfacing to biological systems, and the ability to store mechanical information. However, the facile incorporation of advanced DNA motifs into polymer networks and achieving robustness in application settings remain difficult. Herein, we introduce one-component DNA mechanoprobes that can be easily polymerized into polymer hydrogels and even elastomers to allow strain-induced fluorescence sensing. The all-in-one mechanoprobe contains a DNA hairpin for programmable force sensing, an internal fluorophore-quencher pair as a reporter, and methacrylamide groups on both ends for rapid and facile photopolymerization into networks based on the nontoxic water-soluble monomer methoxy triethylene glycol acrylate (mTEGA). In addition to mechanosensing hydrogels, we utilize the low Tg of p(mTEGA) to develop the first bulk elastomer materials with DNA force sensors, which show high elasticity and stronger mechanofluorescence. The system makes decisive steps forward for DNA-based mechanoprobes by overcoming the classical multicomponent design of such probes, allowing photopolymerization useful for the design of complex objects or even 3D printing and demonstrating that such motifs may even be useful in dry bulk materials.

DOI: https://doi.org/10.1021/acsmacrolett.1c00211
ACS Macro Lett. 2021 Jul 20. 10(7): 886-893

Cationic Bottlebrush Polymers Outperform Linear Polycation Analogues for pDNA Delivery and Gene Expression.

Rishad J Dalal, Ramya Kumar, Monica Ohnsorg, Mary Brown, Theresa M Reineke.

Cationic polymer vehicles have emerged as promising platforms for nucleic acid delivery because of their scalability, biocompatibility, and chemical versatility. Advancements in synthetic polymer chemistry allow us to precisely tune chemical functionality with various macromolecular architectures to increase the efficacy of nonviral-based gene delivery. Herein, we demonstrate the first cationic bottlebrush polymer-mediated pDNA delivery by comparing unimolecular, synthetically defined bottlebrush polymers to their linear building blocks. We successfully synthesized poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA) bottlebrushes through ring-opening metathesis polymerization to afford four bottlebrush polymers with systematic increases in backbone degree of polymerization (Nbb = 13, 20, 26, and 37), while keeping the side-chain degree of polymerization constant (Nsc = 57). Physical and chemical properties were characterized, and subsequently, the toxicity and delivery efficiency of pDNA into HEK293 cells were evaluated. The bottlebrush-pDNA complex (bottleplex) with the highest Nbb, BB_37, displayed up to a 60-fold increase in %EGFP+ cells in comparison to linear macromonomer. Additionally, we observed a trend of increasing EGFP expression with increasing polymer molecular weight. Bottleplexes and polyplexes both displayed high pDNA internalization as measured via payload enumeration per cell; however, quantitative confocal analysis revealed that bottlebrushes were able to shuttle pDNA into and around the nucleus more successfully than pDNA delivered via linear analogues. Overall, a canonical cationic monomer, such as DMAEMA, synthesized in the form of cationic bottlebrush polymers proved to be far more efficient in functional pDNA delivery and expression than linear pDMAEMA. This work underscores the importance of architectural modifications and the potential of bottlebrushes to serve as effective biomacromolecule delivery vehicles.

DOI: https://doi.org/10.1021/acsmacrolett.1c00335
Sci Adv. 2022 May 13. 8(19): eabo0946

A sustainable single-component "Silk nacre".

Zongpu Xu, Mingrui Wu, Weiwei Gao, Hao Bai.

Synthetic composite materials constructed by hybridizing multiple components are typically unsustainable due to inadequate recyclability and incomplete degradation. In contrast, biological materials like silk and bamboo assemble pure polymeric components into sophisticated multiscale architectures, achieving both excellent performance and full degradability. Learning from these natural examples of bio-based "single-component" composites will stimulate the development of sustainable materials. Here, we report a single-component "Silk nacre," where nacre's typical "brick-and-mortar" structure has been replicated with silk fibroin only and by a facile procedure combining bidirectional freezing, water vapor annealing, and densification. The biomimetic design endows the Silk nacre with mechanical properties superior to those of homogeneous silk material, as well as to many frequently used polymers. In addition, the Silk nacre shows controllable plasticity and complete biodegradability, representing an alternative substitute to conventional composite materials.

DOI: https://doi.org/10.1126/sciadv.abo0946
ACS Nano. 2022 May 10.

Nanosized Janus AuNR-Pt Motor for Enhancing NIR-II Photoacoustic Imaging of Deep Tumor and Pt2+ Ion-Based Chemotherapy.

Qingqing Li, Luntao Liu, Hongqi Huo, Lichao Su, Ying Wu, Hongxin Lin, Xiaoguang Ge, Jing Mu, Xuan Zhang, Liting Zheng, Jibin Song.

  Synthetic micro/nanomotors have great potential in deep tissue imaging and in vivo drug delivery because of their active motion ability. However, applying nanomotors with a size less than 100 nm to in vivo imaging and therapy is one of the core changes in this field. Herein, a nanosized hydrogen peroxide (H2O2)-driven Janus gold nanorod-platinum (JAuNR-Pt) nanomotor is developed for enhancing the second near-infrared region (NIR-II) photoacoustic (PA) imaging of deep tissues of tumors and for effective tumor treatment. The JAuNR-Pt nanomotor is prepared by depositing platinum (Pt) on one end of a gold nanorod with varying proportions of Pt shell coverage, including 10%, 25%, 50%, 75%, and 100%. The JAuNR-Pt nanomotor with Pt shell coverage proportions of 50% exhibits the highest diffusion coefficient (De), and it can rapidly move in the presence of H2O2. The self-propulsion of JAuNR-Pt nanomotor enhances cellular uptake, accelerates lysosomal escape, and facilitates continuous release of cytotoxic Pt2+ ions to the nucleus, causing DNA damage and cell apoptosis. The JAuNR-Pt nanomotor presents deep penetration and enhanced accumulation in tumors as well as high tumor treatment effect. Therefore, this work displays deep tumor imaging and an excellent antitumor effect, providing an effective tool for accurate diagnosis and treatment of diseases.

Keywords:  Janus nanoparticle; NIR-II; chemotherapy; nanomotor; photoacoustic imaging

DOI:  https://doi.org/10.1021/acsnano.2c00732
ACS Nano. 2022 May 09.

An Injectable Peptide Hydrogel Constructed of Natural Antimicrobial Peptide J-1 and ADP Shows Anti-Infection, Hemostasis, and Antiadhesion Efficacy.

Jingjing Zhou, Hanru Zhang, Muhammad Subaan Fareed, Yuhang He, Yaqi Lu, Changyan Yang, Zhaopeng Wang, Jie Su, Panpan Wang, Wenjin Yan, Kairong Wang.

  Postoperative adhesion is a common complication of abdominal surgery, which always has many adverse effects in patients. At present, there is still a lack of effective treatment measures and materials to prevent adhesion in the clinics. Herein, we report the potential use of J-1-ADP hydrogel formed by natural antimicrobial peptide jelleine-1 (J-1) self-assembling in adenosine diphosphate (ADP) sodium solution to prevent postsurgery adhesion formation. J-1-ADP hydrogel was found to have good antimicrobial activity against the bacteria and fungi tested and can be used to prevent tissue infection, which was thought to be one of the incitements of adhesion. Due to ADP being a platelet-activating factor, J-1-ADP hydrogel showed significant hemostatic activity in vitro verified by whole blood coagulation, plasma coagulation, platelet activation, and platelet adhesion assays. Further, it showed potent hemostatic activity in a mouse liver hemorrhage model. Bleeding was believed to be a cause of the formation of postsurgery adhesion. J-1-ADP hydrogel had a significant antiadhesion effect in a rat side wall defect-cecum abrasion model. In addition, it had good biocompatibility and degradation properties. So the present study may provide an alternative strategy for designing antimicrobial peptide hydrogel material to prevent postoperative adhesion formation in the clinic.

Keywords:  ADP; anti-adhesion; antimicrobial peptide jelleine-1; hemostatic activity; hydrogel

DOI:  https://doi.org/10.1021/acsnano.1c11206
J Control Release. 2022 May 09. pii: S0168-3659(22)00274-7. [Epub ahead of print]

Dual antimicrobial-loaded biodegradable nanoemulsions for synergistic treatment of wound biofilms.

Ahmed Nabawy, Jessa Marie Makabenta, Suzannah Schmidt-Malan, Jungmi Park, Cheng-Hsuan Li, Rui Huang, Stefano Fedeli, Aritra Nath Chattopadhyay, Robin Patel, Vincent M Rotello.

  Wound biofilm infections caused by multidrug-resistant (MDR) bacteria constitute a major threat to public health; acquired resistance combined with resistance associated with the biofilm phenotype makes combatting these infections challenging. Biodegradable polymeric nanoemulsions that encapsulate two hydrophobic antimicrobial agents (eugenol and triclosan) (TE-BNEs) as a strategy to combat chronic wound infections are reported here. The cationic nanoemulsions efficiently penetrate and accumulate in biofilms, synergistically eradicating MDR bacterial biofilms, including persister cells. Notably, the nanoemulsion platform displays excellent biocompatibility and delays emergence of resistance to triclosan. The TE-BNEs are active in an in vivo murine model of mature MDR wound biofilm infections, with 99% bacterial elimination. The efficacy of this system coupled with prevention of emergence of bacterial resistance highlight the potential of this combination platform to treat MDR wound biofilm infections.

Keywords:  Antimicrobials; In vivo; Multidrug-resistant bacteria; Nanoemulsions; Wound biofilms

DOI:  https://doi.org/10.1016/j.jconrel.2022.05.013
ACS Nano. 2022 May 13.

Infant Skin Friendly Adhesive Hydrogel Patch Activated at Body Temperature for Bioelectronics Securing and Diabetic Wound Healing.

Yanan Jiang, Xin Zhang, Wei Zhang, Menghao Wang, Liwei Yan, Kefeng Wang, Lu Han, Xiong Lu.

  Adhesive-caused injury is a great threat for infants with premature skin or diabetic patients with fragile skin because extra-strong adhesion might incur pain, inflammation, and exacerbate trauma upon removal. Herein, we present a skin-friendly adhesive hydrogel patch based on protein-polyphenol complexation strategy, which leads to a thermoresponsive network sensitive to body temperature. The adhesion of the hydrogel is smartly activated after contacting with warm skin, whereas the painless detachment is easily realized by placing an ice bag on the surface of the hydrogel. The hydrogel exhibits an immunomodulatory performance that prevents irritation and allergic reactions during long-period contact with the skin. Thus, the hydrogel patch works as a conformable and nonirritating interface to guarantee nondestructively securing bioelectronics on infant skin for healthcare. Furthermore, the hydrogel patch provides gentle adhesion to wounded skin and provides a favorable environment to speed up the healing process for managing diabetic wounds.

Keywords:  adhesive hydrogel; detachable hydrogel; diabetic wound; polyphenol chemistry; wound dressing

DOI:  https://doi.org/10.1021/acsnano.2c00662
ACS Nano. 2022 May 13.

Shape Designed Implanted Drug Delivery System for In Situ Hepatocellular Carcinoma Therapy.

Chaochao Zhao, Qin Shi, Hu Li, Xi Cui, Yuan Xi, Yu Cao, Zhuo Xiang, Feng Li, Jinyan Sun, Jiacheng Liu, Tongqiang Li, Wei Wei, Bin Xiong, Zhou Li.

  In this study, an intelligent drug delivery system (DDS) based on implanted triboelectric nanogenerator (iTENG) and red blood cell (RBC) is established for in situ hepatocellular carcinoma (HCC) therapy. Apatinib (APA), as an oral antitumor drug, which can inhibit the expression of vascular endothelial growth factor receptor-2 (VEGFR2) is loaded inside RBC, realizing the transform from oral formulation to injection preparation. Multishape designed iTENG adapted for different implant sites and environments can harvest biomechanical energy efficiently. The electric field (EF) generated by the iTENG can increase the release of APA, and the release will decrease quickly when the EF disappears, which shows that the DDS is highly controllable. The controllable DDS demonstrates an exciting killing ability of HCC cells both in vitro and in vivo with strikingly reduced APA dosage. After implantation, the self-powered DDS has a prominent therapeutic effect of HCC-bearing rabbits, which is expected to be applied in clinical medicine.

Keywords:  apatinib; drug delivery; hepatocellular carcinoma; self-powered; triboelectric nanogenerator

DOI:  https://doi.org/10.1021/acsnano.2c03768
Adv Healthc Mater. 2022 May 11. e2200648

A Simple and Efficient Strategy for Preparing a Cell-Spheroid-Based Bioink.

Weiyan Sun, Jiahui Zhang, Yechi Qin, Hai Tang, Yi Chen, Weikang Lin, Yunlang She, Kunxi Zhang, Jingbo Yin, Chang Chen.

  Cell spheroids are a promising bioprinting building block that can mimic several physiological conditions in embryonic development. However, it remains challenging to efficiently prepare cell-spheroid-based bioink (Sph-bioink) with favorable printability and spheroid fusion ability. In this work, a poly(N-isopropylacrylamide) (PNIPAAm)-based porous hydrogel was developed as an "all-in-one" platform for Sph-bioink preparation. On the one hand, the non-adhesive porous structure in hydrogels is an effective tool for fabricating adipose-derived stem cell (ASC) spheroids in high yield, and the hydrogel itself also serves as a "carrier" for conveniently transferring cell spheroids to the bioprinter. On the other hand, the integration of redox/thermo-responsiveness allows the hydrogel to shift from a solid spheroid-making tool to an extrudable bioprinting medium that is sensitive to temperature. These features enabled a simple procedure for preparing Sph-bioink, in which the cell spheroids were densely packed to retain fusion capability. The present study also demonstrated that ASC spheroids formed in hydrogels have good biological preservation and superior chondrogenic differentiation, and verified the feasibility of using Sph-bioink to build custom-shaped mature cartilage. In conclusion, this strategy provides a simple, efficient, and standardized approach for Sph-bioink preparation, making it possible to produce tissue-engineered constructs with accelerated maturation and functionalization. This article is protected by copyright. All rights reserved.

Keywords:  bioink; bioprinting; cell spheroid; chondroid; organoid

DOI:  https://doi.org/10.1002/adhm.202200648
ACS Nano. 2022 May 12.

Multilayered Ordered Protein Arrays Self-Assembled from a Mixed Population of Virus-like Particles.

Masaki Uchida, Nicholas E Brunk, Nathasha D Hewagama, Byeongdu Lee, Peter E Prevelige, Vikram Jadhao, Trevor Douglas.

  Biology shows many examples of spatially controlled assembly of cells and biomacromolecules into hierarchically organized structures, to which many of the complex biological functions are attributed. While such biological structures have inspired the design of synthetic materials, it is still a great challenge to control the spatial arrangement of individual building blocks when assembling multiple types of components into bulk materials. Here, we report self-assembly of multilayered, ordered protein arrays from mixed populations of virus-like particles (VLPs). We systematically tuned the magnitude of the surface charge of the VLPs via mutagenesis to prepare four different types of VLPs for mixing. A mixture of up to four types of VLPs selectively assembled into higher-order structures in the presence of oppositely charged dendrimers during a gradual lowering of the ionic strength of the solution. The assembly resulted in the formation of three-dimensional ordered VLP arrays with up to four distinct layers including a central core, with each layer comprising a single type of VLP. A coarse-grained computational model was developed and simulated using molecular dynamics to probe the formation of the multilayered, core-shell structure. Our findings establish a simple and versatile bottom-up strategy to synthesize multilayered, ordered materials by controlling the spatial arrangement of multiple types of nanoscale building blocks in a one-pot fabrication.

Keywords:  core-shell structures; electrostatic interactions; hierarchical structures; multilayered materials; ordered protein arrays; self-assembly; virus-like particles

DOI:  https://doi.org/10.1021/acsnano.1c11272
Nat Commun. 2022 May 11. 13(1): 2582

PERSIST platform provides programmable RNA regulation using CRISPR endoRNases.

Breanna DiAndreth, Noreen Wauford, Eileen Hu, Sebastian Palacios, Ron Weiss.

Regulated transgene expression is an integral component of gene therapies, cell therapies and biomanufacturing. However, transcription factor-based regulation, upon which most applications are based, suffers from complications such as epigenetic silencing that limit expression longevity and reliability. Constitutive transgene transcription paired with post-transcriptional gene regulation could combat silencing, but few such RNA- or protein-level platforms exist. Here we develop an RNA-regulation platform we call "PERSIST" which consists of nine CRISPR-specific endoRNases as RNA-level activators and repressors as well as modular OFF- and ON-switch regulatory motifs. We show that PERSIST-regulated transgenes exhibit strong OFF and ON responses, resist silencing for at least two months, and can be readily layered to construct cascades, logic functions, switches and other sophisticated circuit topologies. The orthogonal, modular and composable nature of this platform as well as the ease in constructing robust and predictable gene circuits promises myriad applications in gene and cell therapies.

DOI: https://doi.org/10.1038/s41467-022-30172-3
Sci Adv. 2022 May 13. 8(19): eabm1175

Fully implantable wireless batteryless vascular electronics with printed soft sensors for multiplex sensing of hemodynamics.

Robert Herbert, Hyo-Ryoung Lim, Bruno Rigo, Woon-Hong Yeo.

The continuous monitoring of hemodynamics attainable with wireless implantable devices would improve the treatment of vascular diseases. However, demanding requirements of size, wireless operation, and compatibility with endovascular procedures have limited the development of vascular electronics. Here, we report an implantable, wireless vascular electronic system, consisting of a multimaterial inductive stent and printed soft sensors capable of real-time monitoring of arterial pressure, pulse rate, and flow without batteries or circuits. Developments in stent design achieve an enhanced wireless platform while matching conventional stent mechanics. The fully printed pressure sensors demonstrate fast response times, high durability, and sensing at small bending radii. The device is monitored via inductive coupling at communication distances notably larger than prior vascular sensors. The wireless electronic system is validated in artery models, while minimally invasive catheter implantation is demonstrated in an in vivo rabbit study. Overall, the vascular system offers an adaptable framework for comprehensive monitoring of hemodynamics.

DOI: https://doi.org/10.1126/sciadv.abm1175
ACS Macro Lett. 2021 Dec 21. 10(12): 1563-1569

Self-Assembly of Poly(Janus particle)s into Unimolecular and Oligomeric Spherical Micelles.

Zhan Li, Zongxin Li, Junfei Hu, Xingwei Feng, Minghua Zhang, Gaigai Duan, Ruimeng Zhang, Yiwen Li.

Using shape-persistent Janus particles to construct poly(Janus particle)s and studying their self-assembly behaviors are of great interest, but remain largely unexplored. In this work, we reported a type of amphiphiles constructed by the ring-opening metathesis polymerization of nonspherical molecular Janus particles (APOSS-BPOSS), called poly(Janus particle)s (poly(APOSS-BPOSS)n, n = 12, 17, 22, and 35, and Mn = 35-100 kg/mol). Unlike traditional bottlebrush polymers consisting of flexible side chains, these poly(Janus particles) consist of rigid hydrophilic and hydrophobic polyhedral oligomeric silsesquioxane (POSS) cages as side chains. Interestingly, instead of maintaining an expected extended chain conformation, they could also collapse and then self-assemble to form unconventional unimolecular or oligomeric spherical micelles in solutions with a feature size smaller than 7 nm. More importantly, unlike traditional amphiphilic polymer brushes that could form unimolecular micelles at a relatively high degree of polymerization by self-assembly, these poly(Janus particles)s could accomplish self-assembly at a quite low degree of polymerization because of their unique chemical structure and molecular topology. The formation of unimolecular and oligomeric micelles was also further confirmed by dissipative particle dynamics simulations. This study of introducing the POSS-based poly(Janus particle)s as a class of shape amphiphiles will provide a model system for generating unimolecular and oligomeric micellar nanostructures through solution self-assembly.

DOI: https://doi.org/10.1021/acsmacrolett.1c00620
Nat Commun. 2022 May 12. 13(1): 2633

Tailored modular assembly derived self-healing polythioureas with largely tunable properties covering plastics, elastomers and fibers.

Yan Mei Li, Ze Ping Zhang, Min Zhi Rong, Ming Qiu Zhang.

To impart self-healing polymers largely adjustable dynamicity and mechanical performance, here we develop libraries of catalyst-free reversible polythioureas directly from commodity 1,4-phenylene diisothiocyanate and amines via facile click chemistry based modular assembly. By using the amine modules with various steric hindrances and flexibilities, the reversible thiourea units acquire triggering temperatures from room temperature to 120 °C. Accordingly, the derived self-healable, recyclable and controlled degradable dynamically crosslinked polythioureas can take effect within wide temperature range. Moreover, mechanical properties of the materials can be tuned covering plastics, elastomers and fibers using (i) different assemble modules or (ii) solid-state stretching. Particularly, unidirectional stretching leads to the record-high tensile strength of 266 MPa, while bidirectional stretching provides the materials with biaxial strengths up to over 120 MPa. The molecular mechanism and technological innovations discussed in this work may benefit promotion and application of self-healing polymers towards greatly diverse demands and scenarios.

DOI: https://doi.org/10.1038/s41467-022-30364-x
Nanoscale Horiz. 2022 May 09.

Intelligent and robust DNA robots capable of swarming into leakless nonlinear amplification in response to a trigger.

Shaofei Li, Yizhuang Cheng, Miao Qin, Guoliang Zhou, Pan Li, Liangbao Yang.

Nonlinear DNA signal amplification with an enzyme-free isothermal self-assembly process is uniquely useful in nanotechnology and nanomedicine. However, progress in this direction is hampered by the lack of effective design models of leak-resistant DNA building blocks. Here, we propose two conceptual models of intelligent and robust DNA robots to perform a leakless nonlinear signal amplification in response to a trigger. Two conceptual models are based on super-hairpin nanostructures, which are designed by innovating novel principles in methodology and codifying them into embedded programs. The dynamical and thermodynamical analyses reveal the critical elements and leak-resistant mechanisms of the designed models, and the leak-resistant behaviors of the intelligent DNA robots and morphologies of swarming into nonlinear amplification are separately verified. The applications of the designed models are also illustrated in specific signal amplification and targeted payload enrichment via integration with an aptamer, a fluorescent molecule and surface-enhanced Raman spectroscopy. This work has the potential to serve as design guidelines of intelligent and robust DNA robots and leakless nonlinear DNA amplification, and also as the design blueprint of cargo delivery robots with the performance of swarming into nonlinear amplification in response to a target automatically, facilitating their future applications in biosensing, bioimaging and biomedicine.

DOI: https://doi.org/10.1039/d2nh00018k