bims-drudre 2022-12-25 papers

bims-drudre

Biomed News

on Targeted drug delivery and programmed release mechanisms

Issue of 2022–12–25
24 papers selected by
Ceren Kimna, Technical University of Munich

Extremophile-based biohybrid micromotors for biomedical operations in harsh acidic environments.
Oncolytic Hairpin DNA Pair: Selective Cytotoxic Inducer through MicroRNA-Triggered DNA Self-Assembly.
Normalizing the Immune Macroenvironment via Debulking Surgery to Strengthen Tumor Nanovaccine Efficacy and Eliminate Metastasis.
Dissolvable Self-locking Microneedle Patches Integrated with Immunomodulators for Cancer Immunotherapy.
Design of a self-driven probiotic-CRISPR/Cas9 nanosystem for sono-immunometabolic cancer therapy.
An intelligent, autocatalytic, DNAzyme biocircuit for amplified imaging of intracellular microRNAs.
Microrobots for Targeted Delivery and Therapy in Digestive System.
Dressing bacteria with a hybrid immunoactive nanosurface to elicit dual anticancer and antiviral immunity.
Systemic enhancement of antitumour immunity by peritumourally implanted immunomodulatory macroporous scaffolds.
pH-Responsive Charge-Conversion Progelator Peptides.
Multi-micron crisscross structures grown from DNA-origami slats.
Delivering mRNA to Secondary Lymphoid Tissues by Phosphatidylserine-loaded Lipid Nanoparticles.
Treatment of peanut allergy and colitis in mice via the intestinal release of butyrate from polymeric micelles.
Intracellular phase separation of globular proteins facilitated by short cationic peptides.
Unmanned Aerial Vehicle-Mediated Drug Delivery for First Aid.
Assembly of Immunogenic Protein Particles toward Advanced Synthetic Vaccines.
Nanoparticles with ultrasound-induced afterglow luminescence for tumour-specific theranostics.
Peripheral Microneedle Patch for First-Aid Hemostasis.
Adipose-targeted triiodothyronine therapy counteracts obesity-related metabolic complications and atherosclerosis with negligible side effects.
Cationic lipid modification of DNA tetrahedral nanocages enhances their cellular uptake.
Colonic drug delivery: Formulating the next generation of colon-targeted therapeutics.
M1/M2 re-polarization of kaempferol biomimetic NPs in anti-inflammatory therapy of atherosclerosis.
A deep-learning model for transforming the style of tissue images from cryosectioned to formalin-fixed and paraffin-embedded.
Serum metabolic traits reveal therapeutic toxicities and responses of neoadjuvant chemoradiotherapy in patients with rectal cancer.

Sci Adv. 2022 Dec 23. 8(51): eade6455

Extremophile-based biohybrid micromotors for biomedical operations in harsh acidic environments.

Fangyu Zhang, Zhengxing Li, Yaou Duan, Hao Luan, Lu Yin, Zhongyuan Guo, Chuanrui Chen, Mingyao Xu, Weiwei Gao, Ronnie H Fang, Liangfang Zhang, Joseph Wang.

The function of robots in extreme environments is regarded as one of the major challenges facing robotics. Here, we demonstrate that acidophilic microalgae biomotors can maintain their swimming behavior over long periods of time in the harsh acidic environment of the stomach, thus enabling them to be applied for gastrointestinal (GI) delivery applications. The biomotors can also be functionalized with a wide range of cargos, ranging from small molecules to nanoparticles, without compromising their ability to self-propel under extreme conditions. Successful GI delivery of model payloads after oral administration of the acidophilic algae motors is confirmed using a murine model. By tuning the surface properties of cargos, it is possible to modulate their precise GI localization. Overall, our findings indicate that multifunctional acidophilic algae-based biomotors offer distinct advantages compared to traditional biohybrid platforms and hold great potential for GI-related biomedical applications.

DOI: https://doi.org/10.1126/sciadv.ade6455
J Am Chem Soc. 2022 Dec 20.

Oncolytic Hairpin DNA Pair: Selective Cytotoxic Inducer through MicroRNA-Triggered DNA Self-Assembly.

Kunihiko Morihiro, Hiraki Osumi, Shunto Morita, Takara Hattori, Manami Baba, Naoki Harada, Riuko Ohashi, Akimitsu Okamoto.

Artificial nucleic acids have attracted much attention as potential cancer immunotherapeutic materials because they are recognized by a variety of extracellular and intracellular nucleic acid sensors and can stimulate innate immune responses. However, their low selectivity for cancer cells causes severe systemic immunotoxicity, making it difficult to use artificial nucleic acid molecules for immune cancer therapy. To address this challenge, we herein introduce a hairpin DNA assembly technology that enables cancer-selective immune activation to induce cytotoxicity. The designed artificial DNA hairpins assemble into long nicked double-stranded DNA triggered by intracellular microRNA-21 (miR-21), which is overexpressed in various types of cancer cells. We found that the products from the hairpin DNA assembly selectively kill miR-21-abundant cancer cells in vitro and in vivo based on innate immune activation. Our approach is the first to allow selective oncolysis derived from intracellular DNA self-assembly, providing a powerful therapeutic modality to treat cancer.

DOI: https://doi.org/10.1021/jacs.2c08974
ACS Nano. 2022 Dec 19.

Normalizing the Immune Macroenvironment via Debulking Surgery to Strengthen Tumor Nanovaccine Efficacy and Eliminate Metastasis.

Nana Ma, Zhiqiang Chen, Guangna Liu, Yale Yue, Yao Li, Keman Cheng, Xiaotu Ma, Qingqing Feng, Jie Liang, Tianjiao Zhang, Xiaoyu Gao, Xinwei Wang, Xinjing Guo, Fei Zhu, Guangjun Nie, Xiao Zhao.

  In tumor nanovaccines, nanocarriers enhance the delivery of tumor antigens to antigen-presenting cells (APCs), thereby ensuring the robust activation of tumor antigen-specific effector T-cells to kill tumor cells. Through employment of their high immunogenicity and nanosize, we have developed a "Plug-and-Display" delivery platform on the basis of bacterial outer membrane vesicles (OMVs) for tumor nanovaccines (NanoVac), which can rapidly display different tumor antigens and efficiently eliminate lung metastases of melanoma. In this study, we first upgraded the NanoVac to increase their antigen display efficiency. However, we found that the presence of a subcutaneous xenograft seriously hampered the efficiency of NanoVac to eliminate lung metastases, with the subcutaneous xenograft mimicking the primary tumor burden in clinical practice. The primary tumor secreted significant amounts of granulocyte colony-stimulating factor (G-CSF) and altered the epigenetic features of granulocyte monocyte precursor cells (GMPs) in the bone marrow, thus disrupting systemic immunity, particularly the function of APCs, and ultimately resulting in NanoVac failure to affect metastases. These changes in the systemic immune macroenvironment were plastic, and debulking surgery of primary tumor resection reversed the dysfunction of APCs and failure of NanoVac. These results demonstrate that, in addition to the formulation design of the tumor nanovaccines themselves, the systemic immune macroenvironment incapacitated by tumor development is another key factor that cannot be ignored to affect the efficiency of tumor nanovaccines, and the combination of primary tumor resection with NanoVac is a promising radical treatment for widely metastatic tumors.

Keywords:  G-CSF; antigen presentation; debulking surgery; metastasis elimination; systemic immunity; tumor nanovaccines

DOI:  https://doi.org/10.1021/acsnano.2c08880
Adv Mater. 2022 Dec 17. e2209966

Dissolvable Self-locking Microneedle Patches Integrated with Immunomodulators for Cancer Immunotherapy.

Seung-Hwan Joo, Jaehyun Kim, Juhyeong Hong, Shayan Fakhraei Lahiji, Yong-Hee Kim.

  Advancements in micro-resolution 3D printers have significantly facilitated the development of highly complex mass-producible drug delivery platforms. Conventionally, due to the limitations of micro-milling machineries, dissolvable microneedles (MNs) were mainly fabricated in cone-shaped geometry with limited drug delivery accuracy. Herein, to overcome the limitations of conventional MNs, a novel projection micro-stereolithography 3D printer-based self-locking MN for precise skin insertion, adhesion, and transcutaneous microdose drug delivery is presented. The geometry of self-locking MN consists of a sharp skin-penetrating tip, a wide skin interlocking body, and a narrow base with mechanical supports fabricated over a flexible hydrocolloid patch to improve the accuracy of skin penetration into irregular surfaces. Melanoma, a type of skin cancer, was selected as the model for the investigation of self-locking MNs due to its irregular and uneven surface. In vivo immunotherapy efficacy was evaluated by integrating SD-208, a novel transforming growth factor-β (TGF-β) inhibitor that suppresses the proliferation and metastasis of tumors, and anti-PD-L1 (αPD-L1 Ab), an immune checkpoint inhibitor that induces T cell-mediated tumor cell death, into self-locking MNs and compared with intratumoral injection. Evaluation of (αPD-L1 Ab)/SD-208 delivery effectiveness in B16F10 melanoma-bearing mice model confirmed significantly improved dose efficacy of self-locking MNs compared with intratumoral injection. This article is protected by copyright. All rights reserved.

Keywords:  Dissolvable microneedle; Immunomodulation; Melanoma immunotherapy; Micro-stereolithography 3D printing; Self-locking microneedle; Transcutaneous drug delivery

DOI:  https://doi.org/10.1002/adma.202209966
Nat Commun. 2022 Dec 22. 13(1): 7903

Design of a self-driven probiotic-CRISPR/Cas9 nanosystem for sono-immunometabolic cancer therapy.

Jifeng Yu, Bangguo Zhou, Shen Zhang, Haohao Yin, Liping Sun, Yinying Pu, Boyang Zhou, Yikang Sun, Xiaolong Li, Yan Fang, Lifan Wang, Chongke Zhao, Dou Du, Yan Zhang, Huixiong Xu.

Reprogramming the tumor immunosuppressive microenvironment is a promising strategy for improving tumor immunotherapy efficacy. The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 system can be used to knockdown tumor immunosuppression-related genes. Therefore, here, a self-driven multifunctional delivery vector is constructed to efficiently deliver the CRISPR-Cas9 nanosystem for indoleamine 2,3-dioxygenase-1 (IDO1) knockdown in order to amplify immunogenic cell death (ICD) and then reverse tumor immunosuppression. Lactobacillus rhamnosus GG (LGG) is a self-driven safety probiotic that can penetrate the hypoxia tumor center, allowing efficient delivery of the CRISPR/Cas9 system to the tumor region. While LGG efficiently colonizes the tumor area, it also stimulates the organism to activate the immune system. The CRISPR/Cas9 nanosystem can generate abundant reactive oxygen species (ROS) under the ultrasound irradiation, resulting in ICD, while the produced ROS can induce endosomal/lysosomal rupture and then releasing Cas9/sgRNA to knock down the IDO1 gene to lift immunosuppression. The system generates immune responses that effectively attack tumor cells in mice, contributing to the inhibition of tumor re-challenge in vivo. In addition, this strategy provides an immunological memory effect which offers protection against lung metastasis.

DOI: https://doi.org/10.1038/s41467-022-35580-z
Nanoscale. 2022 Dec 19.

An intelligent, autocatalytic, DNAzyme biocircuit for amplified imaging of intracellular microRNAs.

Meirong Cui, Dan Zhang, Qingfu Wang, Jie Chao.

DNAzymes hold great promise as transducing agents for the analysis of intracellular biomarkers. However, their low intracellular delivery efficiency and limited signal amplification capability (including an additional supply of cofactors) hinder their application in low-abundance biomarker analysis. Herein, a general strategy to design an intelligent, autocatalytic, DNAzyme biocircuit is developed for amplified microRNA imaging in living cells. The DNAzyme biocircuit is constructed based on a nanodevice composed of catalytic hairpin assembly (CHA) and DNAzyme biocatalytic functional units, sustained by Au nanoparticles (AuNPs) and MnO2 nanosheets (CD/AM nanodevices). Once the CD/AM nanodevices are endocytosed by cells, the MnO2 nanosheets are reduced by intracellular glutathione (GSH), which not only releases the different units of the DNAzyme circuit, but also generates the cofactor Mn2+ for DNAzyme autocatalysis. The intracellular analytes could trigger the coordinated cross-activation of CHA and autocatalytic DNAzymes on AuNPs, enabling reliable and accurate detection of miRNAs in living cells. This intelligent autocatalytic multilayer DNAzyme biocircuit can effectively avoid signal leakage and obtain high amplification gain, expanding the application of programmable complex DNA nanocircuits in biosensing, nanomaterial assembly, and biomedicine.

DOI: https://doi.org/10.1039/d2nr05165f
ACS Nano. 2022 Dec 19.

Microrobots for Targeted Delivery and Therapy in Digestive System.

Yun Wang, Jie Shen, Stephan Handschuh-Wang, Ming Qiu, Shiwei Du, Ben Wang.

  Untethered miniature robots enable targeted delivery and therapy deep inside the gastrointestinal tract in a minimally invasive manner. By combining actuation systems and imaging tools, significant progress has been made toward the development of functional microrobots. These robots can be actuated by external fields and fuels while featuring real-time tracking feedback toward certain regions and can perform the therapeutic process by rational exertion of the local environment of the gastrointestinal tract (e.g., pH, enzyme). Compared with conventional surgical tools, such as endoscopic devices and catheters, miniature robots feature minimally invasive diagnosis and treatment, multifunctionality, high safety and adaptivity, embodied intelligence, and easy access to tortuous and narrow lumens. In addition, the active motion of microrobots enhances local penetration and retention of drugs in tissues compared to common passive oral drug delivery. Based on the dissimilar microenvironments in the various sections of the gastrointestinal tract, this review introduces the advances of miniature robots for minimally invasive targeted delivery and therapy of diseases along the gastrointestinal tract. The imaging modalities for the tracking and their application scenarios are also discussed. We finally evaluate the challenges and barriers that retard their applications and hint on future research directions in this field.

Keywords:  gastrointestinal tract; magnetic actuation; microrobots; self-propulsion; self-propulsion, endoscopy, fluoroscopy; targeted delivery

DOI:  https://doi.org/10.1021/acsnano.2c04716
Adv Mater. 2022 Dec 23. e2210949

Dressing bacteria with a hybrid immunoactive nanosurface to elicit dual anticancer and antiviral immunity.

Ying Liu, Mengmeng Zhang, Xinyue Wang, Fengmin Yang, Zhenping Cao, Lu Wang, Jinyao Liu.

  Approaches capable of simultaneously treating cancer and preventing susceptible patients from lethal infections, such as coronavirus disease 2019, are highly desirable but have proven to be difficult. Here, dressing bacteria with a hybrid immunoactive nanosurface is reported to elicit dual anticancer and antiviral immunity. A combination of checkpoint blocking antibody and virus-specific antigen is covalently conjugated to polydopamine nanoparticles, which can be anchored onto bacterial surface, by a one-step in-situ polymerization of dopamine under a cell-friendly condition. By virtue of the ability to colonize and penetrate deep tumor tissue, dressed bacteria enable sustained release and expanded exposure of carried immunoactivators to stimulate immune cells. In addition to a carrier role, bacteria are able to further provoke innate immunity due to native immunogenicity of the pathogen-associated molecular patterns. Immunization with dressed bacteria promote the maturation and activation of antigen-presenting cells, which induces robust humoral and cellular immune responses in tumor-bearing mice. As evidenced by efficient production of viral antigen-specific immunoglobulin G antibody in serum and significantly suppressed tumor growth in different models, dressing bacteria with a hybrid immunoactive nanosurface paves an avenue to prepare next-generation therapeutics for synergistic treatment and prevention. This article is protected by copyright. All rights reserved.

Keywords:  antitumor; antiviral; bacteria; spike protein; αPD1 antibody

DOI:  https://doi.org/10.1002/adma.202210949
Nat Biomed Eng. 2022 Dec 22.

Systemic enhancement of antitumour immunity by peritumourally implanted immunomodulatory macroporous scaffolds.

Fatemeh S Majedi, Mohammad Mahdi Hasani-Sadrabadi, Timothy J Thauland, Sundeep G Keswani, Song Li, Louis-S Bouchard, Manish J Butte.

A tumour microenvironment abundant in regulatory T (Treg) cells aids solid tumours to evade clearance by effector T cells. Systemic strategies to suppress Treg cells or to augment immunity can elicit autoimmune side effects, cytokine storms and other toxicities. Here we report the design, fabrication and therapeutic performance of a biodegradable macroporous scaffold, implanted peritumourally, that releases a small-molecule inhibitor of transforming growth factor β to suppress Treg cells, chemokines to attract effector T cells and antibodies to stimulate them. In two mouse models of aggressive tumours, the implant boosted the recruitment and activation of effector T cells into the tumour and depleted it of Treg cells, which resulted in an 'immunological abscopal effect' on distant metastases and in the establishment of long-term memory that impeded tumour recurrence. We also show that the scaffold can be used to deliver tumour-antigen-specific T cells into the tumour. Peritumourally implanted immunomodulatory scaffolds may represent a general strategy to enhance T-cell immunity and avoid the toxicities of systemic therapies.

DOI: https://doi.org/10.1038/s41551-022-00977-0
Adv Funct Mater. 2021 Mar 24. pii: 2007733. [Epub ahead of print]31(13):

pH-Responsive Charge-Conversion Progelator Peptides.

Andrea S Carlini, Wonmin Choi, Naneki C McCallum, Nathan C Gianneschi.

  A simple strategy for generating stimuli-responsive peptide-based hydrogels via charge-conversion of a self-assembling peptide (SAP) is described. These materials are formulated as soluble, polyanionic peptides, containing maleic acid, citraconic acid, or dimethylmaleic acid masking groups on each lysine residue, which do not form assemblies, but instead flow easily through high gauge needles and catheters. Acid-induced mask hydrolysis renews the zwitterionic nature of the peptides with concomitant and rapid self-assembly via β-sheet formation into rehealable hydrogels. The use of different masks enables one to tune pH responsiveness and assembly kinetics. In anticipation of their potential for in vivo hydrogel delivery and use, progelators exhibit hemocompatibility in whole human blood, and their peptide components are shown to be noncytotoxic. Finally, demonstration of stimuli-induced self-assembly for dye sequestration suggests a simple, non-covalent strategy for small molecule encapsulation in a degradable scaffold. In summary, this simple, scalable masking strategy allows for preparation of responsive, dynamic self-assembling biomaterials. This work sets the stage for implementing biodegradable therapeutic hydrogels that assemble in response to physiological, disease-relevant states of acidosis.

Keywords:  catheter; charge-conversion; hemocompatible; hydrogels; pH-responsive; peptides; self-assembly

DOI:  https://doi.org/10.1002/adfm.202007733
Nat Nanotechnol. 2022 Dec 21.

Multi-micron crisscross structures grown from DNA-origami slats.

Christopher M Wintersinger, Dionis Minev, Anastasia Ershova, Hiroshi M Sasaki, Gokul Gowri, Jonathan F Berengut, F Eduardo Corea-Dilbert, Peng Yin, William M Shih.

Living systems achieve robust self-assembly across a wide range of length scales. In the synthetic realm, nanofabrication strategies such as DNA origami have enabled robust self-assembly of submicron-scale shapes from a multitude of single-stranded components. To achieve greater complexity, subsequent hierarchical joining of origami can be pursued. However, erroneous and missing linkages restrict the number of unique origami that can be practically combined into a single design. Here we extend crisscross polymerization, a strategy previously demonstrated with single-stranded components, to DNA-origami 'slats' for fabrication of custom multi-micron shapes with user-defined nanoscale surface patterning. Using a library of ~2,000 strands that are combinatorially arranged to create unique DNA-origami slats, we realize finite structures composed of >1,000 uniquely addressable slats, with a mass exceeding 5 GDa, lateral dimensions of roughly 2 µm and a multitude of periodic structures. Robust production of target crisscross structures is enabled through strict control over initiation, rapid growth and minimal premature termination, and highly orthogonal binding specificities. Thus crisscross growth provides a route for prototyping and scalable production of structures integrating thousands of unique components (that is, origami slats) that each is sophisticated and molecularly precise.

DOI: https://doi.org/10.1038/s41565-022-01283-1
Adv Healthc Mater. 2022 Dec 19. e2202528

Delivering mRNA to Secondary Lymphoid Tissues by Phosphatidylserine-loaded Lipid Nanoparticles.

Masaki Gomi, Yu Sakurai, Minami Sato, Hiroki Tanaka, Yumi Miyatake, Koichi Fujiwara, Mizuki Watanabe, Satoshi Shuto, Yuta Nakai, Kota Tange, Hiroto Hatakeyama, Hidetaka Akita.

  Lipid nanoparticles (LNPs) are one of the most successful technologies in mRNA delivery. While the liver has been the most frequent target for LNP delivery of mRNA, technologies for delivering mRNA molecules to extrahepatic tissues are also important. Herein, we report on the development of a LNP that targets secondary lymphoid tissues. We designed new types of alcohol-soluble phosphatidylserine (PS) derivatives as materials which target immune cells, and then incorporated them into LNPs using a microfluidic technique with a high degree of scalability and reproducibility. The resulting LNP that contained the synthesized PS delivered mRNA to the spleen much more efficiently compared to a control LNP. A sub-organ analysis revealed that the PS-loaded LNP was extensively taken up by tissue-resident macrophages in the red pulp and the marginal zone of the spleen. Thus, the PS-loaded LNP reported in this study would be a promising strategy for clinical applications that involve delivering mRNA to the spleen. This article is protected by copyright. All rights reserved.

Keywords:  Lipid nanoparticles; lymph node; mRNA delivery; phosphatidylserine; spleen

DOI:  https://doi.org/10.1002/adhm.202202528
Nat Biomed Eng. 2022 Dec 22.

Treatment of peanut allergy and colitis in mice via the intestinal release of butyrate from polymeric micelles.

Ruyi Wang, Shijie Cao, Mohamed Elfatih H Bashir, Lauren A Hesser, Yanlin Su, Sung Min Choi Hong, Andrew Thompson, Elliot Culleen, Matthew Sabados, Nicholas P Dylla, Evelyn Campbell, Riyue Bao, Eric B Nonnecke, Charles L Bevins, D Scott Wilson, Jeffrey A Hubbell, Cathryn R Nagler.

The microbiome modulates host immunity and aids the maintenance of tolerance in the gut, where microbial and food-derived antigens are abundant. Yet modern dietary factors and the excessive use of antibiotics have contributed to the rising incidence of food allergies, inflammatory bowel disease and other non-communicable chronic diseases associated with the depletion of beneficial taxa, including butyrate-producing Clostridia. Here we show that intragastrically delivered neutral and negatively charged polymeric micelles releasing butyrate in different regions of the intestinal tract restore barrier-protective responses in mouse models of colitis and of peanut allergy. Treatment with the butyrate-releasing micelles increased the abundance of butyrate-producing taxa in Clostridium cluster XIVa, protected mice from an anaphylactic reaction to a peanut challenge and reduced disease severity in a T-cell-transfer model of colitis. By restoring microbial and mucosal homoeostasis, butyrate-releasing micelles may function as an antigen-agnostic approach for the treatment of allergic and inflammatory diseases.

DOI: https://doi.org/10.1038/s41551-022-00972-5
Nat Commun. 2022 Dec 22. 13(1): 7882

Intracellular phase separation of globular proteins facilitated by short cationic peptides.

Vivian Yeong, Jou-Wen Wang, Justin M Horn, Allie C Obermeyer.

Phase separation provides intracellular organization and underlies a variety of cellular processes. These biomolecular condensates exhibit distinct physical and material properties. Current strategies for engineering condensate formation include using intrinsically disordered domains and altering protein surface charge by chemical supercharging or site-specific mutagenesis. We propose adding to this toolbox designer peptide tags that provide several potential advantages for engineering protein phase separation in bacteria. Herein, we demonstrate the use of short cationic peptide tags for sequestration of proteins of interest into bacterial condensates and provide a foundational study for their development as tools for condensate engineering. Using a panel of GFP variants, we demonstrate how cationic tag and globular domain charge contribute to intracellular phase separation in E. coli and observe that the tag can affect condensate disassembly at a given net charge near the phase separation boundary. We showcase the broad applicability of these tags by appending them onto enzymes and demonstrating that the sequestered enzymes remain catalytically active.

DOI: https://doi.org/10.1038/s41467-022-35529-2
Adv Mater. 2022 Dec 23. e2208648

Unmanned Aerial Vehicle-Mediated Drug Delivery for First Aid.

Tao Sheng, Rui Jin, Changwei Yang, Ke Qiu, Mingyang Wang, Jiaqi Shi, Jingyu Zhang, Yuman Gao, Qing Wu, Xin Zhou, Hao Wang, Juan Zhang, Qin Fang, Neng Pan, Yanan Xue, Yue Wang, Rong Xiong, Fei Gao, Yuqi Zhang, Haojian Lu, Jicheng Yu, Zhen Gu.

  Timely administration of key medications toward patients with sudden diseases is critical to saving lives. However, laggard transport of first-aid therapeutics and the potential absence of trained people for drug usage always lead to severe injuries or even death. Herein, we develop an unmanned aerial vehicle (UAV)-mediated first aid system for targeted delivery (uFAST). It allows unattended administration of emergency therapeutics-loaded transdermal microneedle patches toward patients to relieve symptoms by a contact-triggered microneedle applicator (CTMA). We have demonstrated the implementability and safety of the uFAST for first aid in a severe hypoglycemic pig model by automatically delivering a glucagon patch with immediate and bioresponsive dual release modes. This platform technique may facilitate the development of UAV-mediated first aid treatments for other sudden diseases. This article is protected by copyright. All rights reserved.

Keywords:  drug delivery; first aid; microneedle; unmanned aerial vehicle

DOI:  https://doi.org/10.1002/adma.202208648
Small. 2022 Dec 23. e2205819

Assembly of Immunogenic Protein Particles toward Advanced Synthetic Vaccines.

Shuxiong Chen, Diana H Quan, Gayathri Sam, Victoria Ozberk, Xiaonan T Wang, Peter Halfmann, Manisha Pandey, Michael F Good, Yoshihiro Kawaoka, Warwick J Britton, Bernd H A Rehm.

  Immunogenic carrier proteins such as the non-toxic diphtheria toxin variant, cross-reacting material 197 (CRM197), are widely used in subunit vaccine formulations to boost immunogenicity of chemically conjugated antigens. Conjugate vaccines are inherently expensive due to laborious manufacturing steps. Here, this work develops a particulate vaccine platform based on using engineered Escherichia coli to assemble CRM197-antigen fusion proteins into discrete submicron-sized particles. This approach enables precise loading of diverse antigens and epitopes enhancing their immunogenicity. A cost-effective, high-yield, and scalable biomanufacturing process is developed. Purified particulate CRM197-antigen vaccines are ambient-temperature stable. CRM197 particles incorporating pathogen-specific antigens or epitopes from SARS-CoV-2, Streptococcus pyogenes (group A), and Mycobacterium tuberculosis induced cell-mediated and humoral immune responses mediating protective immunity in respective animal models of infection. The CRM197 particle vaccine platform is versatile, enabling co-delivery of selected antigens/epitopes together with immunogenic CRM197 as discrete stable particles avoiding laborious manufacture of soluble CRM197 and antigen followed by chemical conjugation.

Keywords:  cross-reacting materials; diphtheria toxin; immunogenic carrier proteins; particulate vaccine; protein assemblies; subunit vaccine

DOI:  https://doi.org/10.1002/smll.202205819
Nat Biomed Eng. 2022 Dec 22.

Nanoparticles with ultrasound-induced afterglow luminescence for tumour-specific theranostics.

Cheng Xu, Jingsheng Huang, Yuyan Jiang, Shasha He, Chi Zhang, Kanyi Pu.

Molecular imaging via afterglow luminescence minimizes tissue autofluorescence and increases the signal-to-noise ratio. However, the induction of afterglow requires the prior irradiation of light, which is attenuated by scattering and absorption in tissue. Here we report the development of organic nanoparticles producing ultrasound-induced afterglow, and their proof-of-concept application in cancer immunotheranostics. The 'sonoafterglow' nanoparticles comprise a sonosensitizer acting as an initiator to produce singlet oxygen and subsequently activate a substrate for the emission of afterglow luminescence, which is brighter and detectable at larger tissue depths (4 cm) than previously reported light-induced afterglow. We formulated sonoafterglow nanoparticles containing a singlet-oxygen-cleavable prodrug for the immune-response modifier imiquimod that specifically turn on in the presence of the inflammation biomarker peroxynitrite, which is overproduced by tumour-associated M1-like macrophages. Systemic delivery of the nanoparticles allowed for sonoafterglow-guided treatment of mice bearing subcutaneous breast cancer tumours. The high sensitivity and depth of molecular sonoafterglow imaging may offer advantages for the real-time in vivo monitoring of physiopathological processes.

DOI: https://doi.org/10.1038/s41551-022-00978-z
Adv Healthc Mater. 2022 Dec 20. e2201697

Peripheral Microneedle Patch for First-Aid Hemostasis.

Jungho Lee, Sebin Park, Phuong Thao Le, Geunho Lee, Hyoun Wook Lee, Gaeun Yun, Juhyeong Jeon, Jeongwoo Park, Duy Tho Pham, Young Sook Park, Hoon Lim, Chulhong Kim, Tae Sik Hwang, Seung Whan Kim, Geunbae Lim.

  Despite the minimized puncture sizes and high efficiency, microneedle (MN) patches have not been used to inject hemostatic drugs into bleeding wounds because they easily destroy capillaries when a tissue is pierced. In this study, a shelf-stable dissolving MN patch is developed to prevent rebleeding during an emergency treatment. A minimally and site-selectively invasive hemostatic drug delivery system is established by using a peripheral MN (p-MN) patch that does not directly intrude the wound site but enables topical drug absorption in the damaged capillaries. The invasiveness of MNs is histologically examined by using a bleeding liver of a Sprague-Dawley rat as an extreme wound model in vivo. The skin penetration force is quantified to demonstrate that the administration of the p-MN patch is milder than that of the conventional MN patch. Hemostatic performance is systematically studied by analyzing bleeding weight and time and comparing them with that of conventional hemostasis methods. The superior performance of a p-MN for the heparin-pretreated SD rat model is demonstrated by intravenous injection in vivo. This article is protected by copyright. All rights reserved.

Keywords:  hemostasis; microneedles; peripheral drug delivery; wound healing

DOI:  https://doi.org/10.1002/adhm.202201697
Nat Commun. 2022 Dec 20. 13(1): 7838

Adipose-targeted triiodothyronine therapy counteracts obesity-related metabolic complications and atherosclerosis with negligible side effects.

Kang Chen, Lai Yee Cheong, Yuan Gao, Yaming Zhang, Tianshi Feng, Qin Wang, Leigang Jin, Eric Honoré, Karen S L Lam, Weiping Wang, Xiaoyan Hui, Aimin Xu.

Thyroid hormone (TH) is a thermogenic activator with anti-obesity potential. However, systemic TH administration has no obvious clinical benefits on weight reduction. Herein we selectively delivered triiodothyronine (T3) to adipose tissues by encapsulating T3 in liposomes modified with an adipose homing peptide (PLT3). Systemic T3 administration failed to promote thermogenesis in brown and white adipose tissues (WAT) due to a feedback suppression of sympathetic innervation. PLT3 therapy effectively obviated this feedback suppression on adrenergic inputs, and potently induced browning and thermogenesis of WAT, leading to alleviation of obesity, glucose intolerance, insulin resistance, and fatty liver in obese mice. Furthermore, PLT3 was much more effective than systemic T3 therapy in reducing hypercholesterolemia and atherosclerosis in apoE-deficient mice. These findings uncover WAT as a viable target mediating the therapeutic benefits of TH and provide a safe and efficient therapeutic strategy for obesity and its complications by delivering TH to adipose tissue.

DOI: https://doi.org/10.1038/s41467-022-35470-4
Nanoscale. 2022 Dec 23.

Cationic lipid modification of DNA tetrahedral nanocages enhances their cellular uptake.

Ramesh Singh, Pankaj Yadav, Hema Naveena A, Dhiraj Bhatia.

Self-assembled DNA nanocages are among the most promising candidates for bioimaging and payload delivery into cells. DNA nanocages have great potential to efficiently address drug resistance and nucleic acid delivery problems due to precise control of their shape and size, and excellent biocompatibility. Although DNA nanostructures demonstrate some cellular uptake, because they bear a highly negative charge, the uptake of tetrahedral nanostructures is hindered by electrostatic repulsion. In this study, we describe a method to enhance the cellular uptake of DNA nanostructures using a binary system containing DNA and a positively charged head group with a hydrophobic lipid chain containing lipids for cellular internalization. Here we represent the functionalization of a model cage, DNA tetrahedron (TD) with a cationic lipid, N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA). Atomic force microscopy (AFM) and other standard characterization techniques were used to explore the co-assembly of the DNA tetrahedron and DOTMA. We revealed a simple confocal microscopy-based approach to show the enhancement in the cellular uptake of DNA nanocages. This new method will find multiple applications in delivery applications such as gene transfection, drug delivery and targeted bioimaging.

DOI: https://doi.org/10.1039/d2nr05749b
J Control Release. 2022 Dec 14. pii: S0168-3659(22)00843-4. [Epub ahead of print]

Colonic drug delivery: Formulating the next generation of colon-targeted therapeutics.

Laura E McCoubrey, Alessia Favaron, Atheer Awad, Mine Orlu, Simon Gaisford, Abdul W Basit.

  Colonic drug delivery can facilitate access to unique therapeutic targets and has the potential to enhance drug bioavailability whilst reducing off-target effects. Delivering drugs to the colon requires considered formulation development, as both oral and rectal dosage forms can encounter challenges if the colon's distinct physiological environment is not appreciated. As the therapeutic opportunities surrounding colonic drug delivery multiply, the success of novel pharmaceuticals lies in their design. This review provides a modern insight into the key parameters determining the effective design and development of colon-targeted medicines. Influential physiological features governing the release, dissolution, stability, and absorption of drugs in the colon are first discussed, followed by an overview of the most reliable colon-targeted formulation strategies. Finally, the most appropriate in vitro, in vivo, and in silico preclinical investigations are presented, with the goal of inspiring strategic development of new colon-targeted therapeutics.

Keywords:  Artificial intelligence and machine learning; Drug delivery systems and the large intestine; Gastrointestinal microbiota and microbiome; Inflammatory bowel disease and drug products; Oral biologics and biopharmaceuticals; Targeting the colon

DOI:  https://doi.org/10.1016/j.jconrel.2022.12.029
J Control Release. 2022 Dec 19. pii: S0168-3659(22)00855-0. [Epub ahead of print]

M1/M2 re-polarization of kaempferol biomimetic NPs in anti-inflammatory therapy of atherosclerosis.

Jianing Zhao, Longbing Ling, Wei Zhu, Tianhao Ying, Tao Yu, Mengmeng Sun, Xuan Zhu, Yuan Du, Leiming Zhang.

  Atherosclerosis (AS), a leading cause of death worldwide, involves chronic macrophage inflammation from its initiation to the emergence of complications. Targeting plaque inflammation by re-polarizing pro-inflammatory M1 to anti-inflammatory M2 could therefore provide a promising strategy to treat AS, but currently available anti-inflammatory drugs limit clinical outcomes. In this study, we found that kaempferol (KPF) is capable of potential anti-inflammation as a novel drug candidate, which has been scarcely reported. Building upon these findings, we fabricated a macrophage-biomimetic KPF delivery platform, abbreviated as KPF@MM-NPs to potentiate therapeutic payloads, wherein the designed ROS-responsive Dextran-g-PBMEO NPs with π-π stacking were coated with macrophage membrane (MM) for effective target and accumulation in atherosclerotic lesions. Therapy of KPF@MM-NPs afforded significant decrease in proliferating macrophage inflammation while went with the reduction of key pro-inflammatory cytokines and re-polarization M1 to M2 phenotype, inducing excellent anti-AS responses in ApoE-/- mice after i.p. delivery. The mechanism of KPF@MM-NPs was further investigated and found it related to block the ROS/NF-κB signaling pathways. Together with as well demonstrated biosafety profiles, this proof-of-concept opens an instructive door for the study of KPF-mediated nanodrugs in treatment of AS based on biomimetic NPs.

Keywords:  Anti-inflammatory therapy; Atherosclerosis; Biomimetic NPs; Kaempferol; M1/M2 re-polarization

DOI:  https://doi.org/10.1016/j.jconrel.2022.12.041
Nat Biomed Eng. 2022 Dec 23.

A deep-learning model for transforming the style of tissue images from cryosectioned to formalin-fixed and paraffin-embedded.

Kutsev Bengisu Ozyoruk, Sermet Can, Berkan Darbaz, Kayhan Başak, Derya Demir, Guliz Irem Gokceler, Gurdeniz Serin, Uguray Payam Hacisalihoglu, Emirhan Kurtuluş, Ming Y Lu, Tiffany Y Chen, Drew F K Williamson, Funda Yılmaz, Faisal Mahmood, Mehmet Turan.

Histological artefacts in cryosectioned tissue can hinder rapid diagnostic assessments during surgery. Formalin-fixed and paraffin-embedded (FFPE) tissue provides higher quality slides, but the process for obtaining them is laborious (typically lasting 12-48 h) and hence unsuitable for intra-operative use. Here we report the development and performance of a deep-learning model that improves the quality of cryosectioned whole-slide images by transforming them into the style of whole-slide FFPE tissue within minutes. The model consists of a generative adversarial network incorporating an attention mechanism that rectifies cryosection artefacts and a self-regularization constraint between the cryosectioned and FFPE images for the preservation of clinically relevant features. Transformed FFPE-style images of gliomas and of non-small-cell lung cancers from a dataset independent from that used to train the model improved the rates of accurate tumour subtyping by pathologists.

DOI: https://doi.org/10.1038/s41551-022-00952-9
Nat Commun. 2022 Dec 17. 13(1): 7802

Serum metabolic traits reveal therapeutic toxicities and responses of neoadjuvant chemoradiotherapy in patients with rectal cancer.

Hongmiao Wang, Huixun Jia, Yang Gao, Haosong Zhang, Jin Fan, Lijie Zhang, Fandong Ren, Yandong Yin, Yuping Cai, Ji Zhu, Zheng-Jiang Zhu.

Neoadjuvant chemoradiotherapy (nCRT) has become the standard treatment for patients with locally advanced rectal cancer (LARC). Therapeutic efficacy of nCRT is significantly affected by treatment-induced diarrhea and hematologic toxicities. Metabolic alternations in cancer therapy are key determinants to therapeutic toxicities and responses, but exploration in large-scale clinical studies remains limited. Here, we analyze 743 serum samples from 165 LARC patients recruited in a phase III clinical study using untargeted metabolomics and identify responsive metabolic traits over the course of nCRT. Pre-therapeutic serum metabolites successfully predict the chances of diarrhea and hematologic toxicities during nCRT. Particularly, levels of acyl carnitines are linked to sex disparity in nCRT-induced diarrhea. Finally, we show that differences in phenylalanine metabolism and essential amino acid metabolism may underlie distinct therapeutic responses of nCRT. This study illustrates the metabolic dynamics over the course of nCRT and provides potential to guide personalized nCRT treatment using responsive metabolic traits.

DOI: https://doi.org/10.1038/s41467-022-35511-y