bims-drudre 2021-07-11 papers

bims-drudre

Biomed News

on Targeted drug delivery and programmed release mechanisms

Issue of 2021–07–11
nine papers selected by
Ceren Kimna, Technical University of Munich

Lure-and-kill macrophage nanoparticles alleviate the severity of experimental acute pancreatitis.
Biomaterial vaccines capturing pathogen-associated molecular patterns protect against bacterial infections and septic shock.
Bacterial cytoplasmic membranes synergistically enhance the antitumor activity of autologous cancer vaccines.
Pulmonary Aerosol Delivery of Let-7b microRNA Confers a Striking Inhibitory Effect on Lung Carcinogenesis through Targeting the Tumor Immune Microenvironment.
Cytosolic Protein Delivery for Intracellular Antigen Targeting Using Supercharged Polypeptide Delivery Platform.
Smartphone-Flashlight-Mediated Remote Control of Rapid Insulin Secretion Restores Glucose Homeostasis in Experimental Type-1 Diabetes.
Detachable Liposomes Combined Immunochemotherapy for Enhanced Triple-Negative Breast Cancer Treatment through Reprogramming of Tumor-Associated Macrophages.
Polymeric Aggregate-Embodied Hybrid Nitric-Oxide-Scavenging and Sequential Drug-Releasing Hydrogel for Combinatorial Treatment of Rheumatoid Arthritis.
Inflammation-Responsive Drug-Loaded Hydrogels with Sequential Hemostasis, Antibacterial, and Anti-Inflammatory Behavior for Chronically Infected Diabetic Wound Treatment.

Nat Commun. 2021 07 06. 12(1): 4136

Lure-and-kill macrophage nanoparticles alleviate the severity of experimental acute pancreatitis.

Qiangzhe Zhang, Julia Zhou, Jiarong Zhou, Ronnie H Fang, Weiwei Gao, Liangfang Zhang.

Acute pancreatitis is a disease associated with suffering and high lethality. Although the disease mechanism is unclear, phospholipase A2 (PLA2) produced by pancreatic acinar cells is a known pathogenic trigger. Here, we show macrophage membrane-coated nanoparticles with a built-in 'lure and kill' mechanism (denoted 'MΦ-NP(L&K)') for the treatment of acute pancreatitis. MΦ-NP(L&K) are made with polymeric cores wrapped with natural macrophage membrane doped with melittin and MJ-33. The membrane incorporated melittin and MJ-33 function as a PLA2 attractant and a PLA2 inhibitor, respectively. These molecules, together with membrane lipids, work synergistically to lure and kill PLA2 enzymes. These nanoparticles can neutralize PLA2 activity in the sera of mice and human patients with acute pancreatitis in a dose-dependent manner and suppress PLA2-induced inflammatory response accordingly. In mouse models of both mild and severe acute pancreatitis, MΦ-NP(L&K) confer effective protection against disease-associated inflammation, tissue damage and lethality. Overall, this biomimetic nanotherapeutic strategy offers an anti-PLA2 treatment option that might be applicable to a wide range of PLA2-mediated inflammatory disorders.

DOI: https://doi.org/10.1038/s41467-021-24447-4
Nat Biomed Eng. 2021 Jul 08.

Biomaterial vaccines capturing pathogen-associated molecular patterns protect against bacterial infections and septic shock.

Michael Super, Edward J Doherty, Mark J Cartwright, Benjamin T Seiler, Fernanda Langellotto, Nikolaos Dimitrakakis, Des A White, Alexander G Stafford, Mohan Karkada, Amanda R Graveline, Caitlin L Horgan, Kayla R Lightbown, Frank R Urena, Chyenne D Yeager, Sami A Rifai, Maxence O Dellacherie, Aileen W Li, Collin Leese-Thompson, Hamza Ijaz, Amanda R Jiang, Vasanth Chandrasekhar, Justin M Scott, Shanda L Lightbown, Donald E Ingber, David J Mooney.

Most bacterial vaccines work for a subset of bacterial strains or require the modification of the antigen or isolation of the pathogen before vaccine development. Here we report injectable biomaterial vaccines that trigger potent humoral and T-cell responses to bacterial antigens by recruiting, reprogramming and releasing dendritic cells. The vaccines are assembled from regulatorily approved products and consist of a scaffold with absorbed granulocyte-macrophage colony-stimulating factor and CpG-rich oligonucleotides incorporating superparamagnetic microbeads coated with the broad-spectrum opsonin Fc-mannose-binding lectin for the magnetic capture of pathogen-associated molecular patterns from inactivated bacterial-cell-wall lysates. The vaccines protect mice against skin infection with methicillin-resistant Staphylococcus aureus, mice and pigs against septic shock from a lethal Escherichia coli challenge and, when loaded with pathogen-associated molecular patterns isolated from infected animals, uninfected animals against a challenge with different E. coli serotypes. The strong immunogenicity and low incidence of adverse events, a modular manufacturing process, and the use of components compatible with current good manufacturing practice could make this vaccine technology suitable for responding to bacterial pandemics and biothreats.

DOI: https://doi.org/10.1038/s41551-021-00756-3
Sci Transl Med. 2021 Jul 07. pii: eabc2816. [Epub ahead of print]13(601):

Bacterial cytoplasmic membranes synergistically enhance the antitumor activity of autologous cancer vaccines.

Long Chen, Hao Qin, Ruifang Zhao, Xiao Zhao, Liangru Lin, Yang Chen, Yixuan Lin, Yao Li, Yuting Qin, Yiye Li, Shaoli Liu, Keman Cheng, Hanqing Chen, Jian Shi, Gregory J Anderson, Yan Wu, Yuliang Zhao, Guangjun Nie.

Cancer vaccines based on resected tumors from patients have gained great interest as an individualized cancer treatment strategy. However, eliciting a robust therapeutic effect with personalized vaccines remains a challenge because of the weak immunogenicity of autologous tumor antigens. Utilizing exogenous prokaryotic constituents that act as adjuvants to enhance immunogenicity is a promising strategy to overcome this limitation. However, nonspecific stimulation of the immune system may elicit an undesirable immunopathological state. To specifically trigger sufficient antitumor reactivity without notable adverse effects, we developed an antigen and adjuvant codelivery nanoparticle vaccine based on Escherichia coli cytoplasmic membranes (EMs) and tumor cell membranes (TMs) from resected autologous tumor tissue. Introduction of the EM into the hybrid membrane nanoparticle vaccines (HM-NPs) induced dendritic cell maturation, thus activating splenic T cells. HM-NPs showed efficacy in immunogenic CT26 colon and 4T1 breast tumor mouse models and also efficiently induced tumor regression in B16-F10 melanoma and EMT6 breast tumor mouse models. Furthermore, HM-NPs provoked a strong tumor-specific immune response, which not only extended postoperative animal survival but also conferred long-term protection (up to 3 months) against tumor rechallenge in a CT26 colon tumor mouse model. Specific depletion of different immune cell populations revealed that CD8+ T and NK cells were crucial to the vaccine-elicited tumor regression. Individualized autologous tumor antigen vaccines based on effective activation of the innate immune system by bacterial cytoplasmic membranes hold great potential for personalized treatment of postoperative patients with cancer.

DOI: https://doi.org/10.1126/scitranslmed.abc2816
Adv Sci (Weinh). 2021 Jul 08. e2100629

Pulmonary Aerosol Delivery of Let-7b microRNA Confers a Striking Inhibitory Effect on Lung Carcinogenesis through Targeting the Tumor Immune Microenvironment.

Qi Zhang, Jing Pan, Donghai Xiong, Yian Wang, Mark Steven Miller, Shizuko Sei, Robert H Shoemaker, Alberto Izzotti, Ming You.

  MicroRNAs are potential candidates for lung cancer prevention and therapy. A major limitation is the lack of an efficient delivery system to directly deliver miRNA to cancer cells while limiting systemic exposure. The delivery of miRNA via inhalation is a potential strategy for lung cancer prevention in high-risk individuals. In this study, the authors investigate the efficacy of aerosolized let-7b miRNA treatment in lung cancer prevention. Let-7b shows significant inhibition of B[a]P-induced lung adenoma with no detectable side effects. Single-cell RNA sequencing of tumor-infiltrating T cells from primary tumors reveals that Let-7b post-transcriptionally suppresses PD-L1 and PD-1 expression in the tumor microenvironment, suggesting that let-7b miRNAs may promote antitumor immunity in vivo. Let-7b treatment decreases the expression of PD-1 in CD8+ T cells and reduces PD-L1 expression in lung tumor cells. The results suggest that this aerosolized let-7b mimic is a promising approach for lung cancer prevention, and that the in vivo tumor inhibitory effects of let-7b are mediated, at least in part, by immune-promoting effects via downregulating PD-L1 in tumors and/or PD-1 on CD8+ T cells. These changes potentiate antitumor CD8+ T cell immune responses, and ultimately lead to tumor inhibition.

Keywords:  immunity; let-7b; lung cancer; miRNA; pulmonary aerosol delivery; single-cell RNA sequencing

DOI:  https://doi.org/10.1002/advs.202100629
Nano Lett. 2021 Jul 06.

Cytosolic Protein Delivery for Intracellular Antigen Targeting Using Supercharged Polypeptide Delivery Platform.

Qun Wang, Yifan Yang, Dingkang Liu, Yue Ji, Xiangdong Gao, Jun Yin, Wenbing Yao.

  Despite the well-recognized clinical success of therapeutic proteins, especially antibodies, their inability to penetrate the cell membrane restricts them to secretory extracellular or membrane-associated targets. Developing a direct cytosolic protein delivery system would offer unique opportunities for intracellular target-related therapeutic proteins. Here, we generated a supercharged polypeptide (SCP) with high cellular uptake efficiency, endosomal escape ability, and good biosafety and developed an SCP with an unnatural amino acid containing the phenylboronic acid (PBA) group, called PBA-SCP. PBA-SCP is capable of potently delivering proteins with various isoelectric points and molecular sizes into the cytosol of living cells without affecting their bioactivities. Importantly, cytosolically delivered antibodies remain functional and are capable of targeting, labeling, and manipulating diverse intracellular antigens. This study demonstrates an efficient and versatile intracellular protein delivery platform, especially for antibodies, and provides new possibilities for expanding protein-based therapeutics to intracellular "undruggable" targets.

Keywords:  antibody delivery; cytosolic protein delivery; intracellular targets; phenylboronic acid; supercharged polypeptide

DOI:  https://doi.org/10.1021/acs.nanolett.1c01190
Small. 2021 Jul 05. e2101939

Smartphone-Flashlight-Mediated Remote Control of Rapid Insulin Secretion Restores Glucose Homeostasis in Experimental Type-1 Diabetes.

Maysam Mansouri, Shuai Xue, Marie-Didiée Hussherr, Tobias Strittmatter, Gieri Camenisch, Martin Fussenegger.

  Emerging digital assessment of biomarkers by linking health-related data obtained from wearable electronic devices and embedded health and fitness sensors in smartphones is opening up the possibility of creating a continuous remote-monitoring platform for disease management. It is considered that the built-in flashlight of smartphones may be utilized to remotely program genetically engineered designer cells for on-demand delivery of protein-based therapeutics. Here, the authors present smartphone-induced insulin release in β-cell line (iβ-cell) technology for traceless light-triggered rapid insulin secretion, employing the light-activatable receptor melanopsin to induce calcium influx and membrane depolarization upon illumination. This iβ-cell-based system enables repeated, reversible secretion of insulin within 15 min in response to light stimulation, with a high induction fold both in vitro and in vivo. It is shown that programmable percutaneous remote control of implanted microencapsulated iβ-cells with a smartphone's flashlight rapidly reverses hyperglycemia in a mouse model of type-1 diabetes.

Keywords:  cell-based therapies; optogenetics; smartphone; synthetic biology; type-1 diabetes

DOI:  https://doi.org/10.1002/smll.202101939
Nano Lett. 2021 Jul 09.

Detachable Liposomes Combined Immunochemotherapy for Enhanced Triple-Negative Breast Cancer Treatment through Reprogramming of Tumor-Associated Macrophages.

Mingshu Chen, Yunqiu Miao, Kun Qian, Xin Zhou, Linmiao Guo, Yu Qiu, Rui Wang, Yong Gan, Xinxin Zhang.

  Triple-negative breast cancer (TNBC) is an aggressive disease with a high recurrence rate and poor outcomes in clinic. In this study, inspired by the enriched innate immune cell type tumor-associated macrophages (TAMs) in TNBC, we proposed a matrix metalloprotease 2 (MMP2) responsive integrated immunochemotherapeutic strategy to deliver paclitaxel (PTX) and anti-CD47 (aCD47) by detachable immune liposomes (ILips). In the TNBC microenvironment, the "two-in-one" ILips facilitated MMP2-responsive release of aCD47 to efficiently polarize M2 macrophages toward the M1 phenotype to enhance phagocytosis against tumor cells and activate the systemic T cell immune response. Together with the immune effect, the detached PTX-loaded liposomes were internalized in MDA-MB-231 cells to synergistically inhibit tumor cell proliferation and metastasis. In the TNBC-bearing mouse model, PTX-loaded ILips demonstrated superior antitumor efficacy against TNBC and inhibited tumor recurrence. Our integrated strategy represents a promising approach to synchronously enhance immune response and tumor-killing effects, improving the therapeutic efficacy against TNBC.

Keywords:  Immunochemotherapy; MMP2 response; liposomes; triple-negative breast cancer; tumor-associated macrophages

DOI:  https://doi.org/10.1021/acs.nanolett.1c01210
Adv Mater. 2021 Jul 08. e2008793

Polymeric Aggregate-Embodied Hybrid Nitric-Oxide-Scavenging and Sequential Drug-Releasing Hydrogel for Combinatorial Treatment of Rheumatoid Arthritis.

Taejeong Kim, Jeeyeon Suh, Won Jong Kim.

  Selective depletion of overproduced nitric oxide (NO) with nanoscavengers is a promising approach for treating rheumatoid arthritis (RA), preventing both oxidative/nitrosative stress and the upregulation of immune cells. However, its practical applications are limited owing to the minimum time interval between intra-articular injections and unwanted off-target NO depletion. Herein, the rational design of an injectable in situ polymeric aggregate-embodied hybrid NO-scavenging and sequential drug-releasing (M-NO) gel platform for the combinatorial treatment of RA by incorporating a "clickable" NO-cleavable cross-linker (DA-NOCCL) is reported. This network is held together with polymeric aggregates to achieve a self-healing capability for visco-supplementation and on-demand dual drug (both hydrophilic and hydrophobic)-releasing properties, depending on the NO concentration. Moreover, consecutive NO-scavenging action reduces pro-inflammatory cytokine levels in lipopolysaccharides-stimulated macrophage cell lines in vitro. Finally, the intra-articularly injected M-NO gel with anti-inflammatory dexamethasone significantly alleviates the symptoms of RA, with negligible toxicity, in animal models. It is believed that this novel M-NO gel platform will provide a guideline for the combinatorial treatment of RA and various NO-related diseases.

Keywords:  hydrogels; nitric oxide; rheumatoid arthritis; stimuli-responsive materials

DOI:  https://doi.org/10.1002/adma.202008793
ACS Appl Mater Interfaces. 2021 Jul 09.

Inflammation-Responsive Drug-Loaded Hydrogels with Sequential Hemostasis, Antibacterial, and Anti-Inflammatory Behavior for Chronically Infected Diabetic Wound Treatment.

Yu Wang, Ye Wu, Linyu Long, Li Yang, Daihua Fu, Cheng Hu, Qingquan Kong, Yunbing Wang.

  Stimuli-responsive hydrogels possess unique advantages in drug delivery due to their variable performance and status based on the external environment. In the present study, a dual-responsive (pH and reactive oxygen species (ROS)) hydrogel was prepared to realize drug release properties under inflammatory stimulation. By grafting 3-carboxy-phenylboronic acid to the gelatin molecular backbone and cross-linking with poly(vinyl alcohol), we successfully synthesized the inflammation-responsive drug-loaded hydrogels after encapsulation with vancomycin-conjugated silver nanoclusters (VAN-AgNCs) and pH-sensitive micelles loaded with nimesulide (NIM). This novel design not only retained the dynamic functions of hydrogels, such as injectability, self-healing, and remodeling, but also realized sequential and on-demand drug delivery at diabetic-infected wound sites. In this work, we found that the hydrogel exhibited excellent biocompatibility and hemostasis properties owing to the enhanced cell-adhesive property of the gelatin component. The significant antibacterial and anti-inflammatory effect of the hydrogel was demonstrated in an in vitro experiment. Moreover, in the in vivo experiment, the hydrogel was found to play a role in promoting infected wound healing through sequential hemostasis and antibacterial and anti-inflammatory processes. Collectively, this inflammation-responsive hydrogel design containing VAN-AgNCs and NIM-loaded micelles has great potential in the application of chronically infected diabetic wound treatment, as well as in other inflammatory diseases.

Keywords:  antibacterial hybrid; drug-loaded micelles; hemostasis; inflammation-responsive; wound healing

DOI:  https://doi.org/10.1021/acsami.1c09889