bims-drudre 2022-10-16 papers

bims-drudre

Biomed News

on Targeted drug delivery and programmed release mechanisms

Issue of 2022–10–16
twenty-one papers selected by
Ceren Kimna, Technical University of Munich

Direct Presentation of Tumor-Associated Antigens to Induce Adaptive Immunity by Personalized Dendritic Cell-Mimicking Nanovaccines.
Fueling DNA Self-Assembly via Gel-Released Regulators.
Living Macrophage-Delivered Tetrapod PdH Nanoenzyme for Targeted Atherosclerosis Management by ROS Scavenging, Hydrogen Anti-inflammation, and Autophagy Activation.
Photothermal Nanozyme-based Microneedle Patch against Refractory Bacterial Biofilm Infection via Iron-actuated Janus Ion Therapy.
Therapeutic Nanocarriers Inhibit Chemotherapy-Induced Breast Cancer Metastasis.
Monobody adapter for functional antibody display on nanoparticles for adaptable targeted delivery applications.
Controllable DNA hybridization by host-guest complexation-mediated ligand invasion.
Enhanced tumor accumulation of multimodal magneto-plasmonic nanoparticles via an implanted micromagnet-assisted delivery strategy.
Calcium Hydride-Based Dressing to Promote Wound Healing.
Porous Silicon-Based Nanomedicine for Simultaneous Management of Joint Inflammation and Bone Erosion in Rheumatoid Arthritis.
Robust and Multifunctional Kirigami Electronics with Tough and Permeable Aramid Nanofiber Framework.
Pro-inflammatory megakaryocyte gene expression in murine models of breast cancer.
Nanoparticle-based modulation of CD4+ T cell effector and helper functions enhances adoptive immunotherapy.
Engineering DNA-based synthetic condensates with programmable material properties, compositions, and functionalities.
Interplay between mucus mobility and alveolar macrophage targeting of surface-modified liposomes.
Gluing blood into gel by electrostatic interaction using a water-soluble polymer as an embolic agent.
Onset of Chirality in Plasmonic Meta-Molecules and Dielectric Coupling.
Metabolic homeostasis-regulated nanoparticles for antibody-independent cancer radio-immunotherapy.
Stimuli-responsive vesicles as distributed artificial organelles for bacterial activation.
A predictive mechanistic model of drug release from surface eroding polymeric nanoparticles.
Immunopeptidomics-based design of mRNA vaccine formulations against Listeria monocytogenes.

Adv Mater. 2022 Oct 11. e2205950

Direct Presentation of Tumor-Associated Antigens to Induce Adaptive Immunity by Personalized Dendritic Cell-Mimicking Nanovaccines.

Jie Zhang, Biao Fan, Guoliang Cao, Wenping Huang, Fuhao Jia, Guangjun Nie, Hai Wang.

  Dendritic cell (DC)-based vaccines are an approved method for inducing potent antigen-specific immune responses to eliminate tumor cells. However, this promising strategy still faces challenges such as tumor-associated antigens (TAAs) loading, lymph node homing, quality control and other limitations. Here, we develop a personalized DC-mimicking nanovaccine (nanoDC) for stimulation of TAAs-specific T cell populations. The nanoDCs are fabricated using nanoparticles with dendritic structure and membranes from mature bone marrow-derived cells (BMDCs). Mature BMDCs are stimulated by nanostructures assembled from Escherichia coli (E. coli) and tumor cells to efficiently deliver TAAs and induce BMDCs maturation through the stimulator of interferon genes (STING) pathway. By maintaining co-stimulatory markers, molecules class I (MHC-I) antigen complexes, and lymphocyte homing receptors, nanoDCs efficiently migrate to lymph nodes and generate potent antigen-specific T cell responses. Consequently, vaccination with nanoDCs strongly inhibit the tumor growth and metastases formation in vivo. In particular, nanoDCs can also induce memory T cells for long-term protective immunity. This study demonstrates that DC-mimicking nanovaccines can trigger adaptive immune protection against tumors for personalized immunotherapy and precision medicine. This article is protected by copyright. All rights reserved.

Keywords:  antigen presentation; cancer immunotherapy; dendritic cell; personalized vaccine

DOI:  https://doi.org/10.1002/adma.202205950
ACS Nano. 2022 Oct 14.

Fueling DNA Self-Assembly via Gel-Released Regulators.

Jenny Le, Dino Osmanovic, Melissa Ann Klocke, Elisa Franco.

  The development of responsive, multicomponent molecular materials requires means to physically separate yet easily couple distinct processes. Here we demonstrate methods to use molecules and reactions loaded into microliter-sized polyacrylamide hydrogels (mini-gels) to control the dynamic self-assembly of DNA nanotubes. We first characterize the UV-mediated release of DNA molecules from mini-gels, changing diffusion rates and minimizing spontaneous leakage of DNA. We then demonstrate that mini-gels can be used as compartments for storage and release of DNA that mediates the assembly or disassembly of DNA nanotubes in a one-pot process and that the speed of DNA release is controlled by the mini-gel porosity. With this approach, we achieve control of assembly and disassembly of nanotubes with distinct kinetics, including a finite delay that is obtained by loading distinct DNA regulators into distinct mini-gels. We finally show that mini-gels can also host and localize enzymatic reactions, by transcribing RNA regulators from synthetic genes loaded in the mini-gels, with diffusion of RNA to the aqueous phase resulting in the activation of self-assembly. Our experimental data are recapitulated by a mathematical model that describes the diffusion of DNA molecules from the gel phase to the aqueous phase in which they control self-assembly of nanotubes. Looking forward, DNA-loaded mini-gels may be further miniaturized and patterned to build more sophisticated storage compartments for use within multicomponent, complex biomolecular materials relevant for biomedical applications and artificial life.

Keywords:  DNA nanotechnology; DNA nanotubes; DNA tiles; UV irradiation; hydrogels; photocleavage; polyacrylamide

DOI:  https://doi.org/10.1021/acsnano.2c05595
ACS Nano. 2022 Oct 11.

Living Macrophage-Delivered Tetrapod PdH Nanoenzyme for Targeted Atherosclerosis Management by ROS Scavenging, Hydrogen Anti-inflammation, and Autophagy Activation.

Ruizhi Hu, Chen Dai, Caihong Dong, Li Ding, Hui Huang, Yu Chen, Bo Zhang.

  Atherosclerosis, driven by chronic inflammation in the artery walls, underlies several severe cardiovascular diseases. However, currently available anti-inflammatory-based strategies for atherosclerosis treatment suffer from compromised therapeutic efficacy and undesirable therapeutic outcome. Herein, a distinct tetrapod needle-like PdH nanozyme was designed and engineered for efficient atherosclerosis treatment by the combinatorial reactive oxygen species (ROS) scavenging, hydrogen anti-inflammation, and autophagy activation. After loading into macrophages and targeted delivery to arterial plaques, these multifunctional nanozymes efficiently decreased the ROS levels and significantly suppressed the inflammation-related pathological process, exerting the distinct antioxidation and anti-inflammatory performance for alleviating atherosclerosis development. Especially and importantly, the specific spiky morphology of the PdH nanoenzyme further triggered a strong autophagy response in macrophages, synergistically maintaining the cellular homeostasis and alleviating atherosclerosis development. Both in vitro and in vivo results confirmed the synergy among the antioxidation, anti-inflammatory, and autophagy activation, suggesting that the combinatorial engineering of nanomedicines with intrinsic multiple therapeutic functions and topology-induced biological effects is highly preferable and effective for achieving the high therapeutic performance and desirable therapeutic outcome on atherosclerosis management and therapy.

Keywords:  PdH; ROS scavenge; atherosclerosis; autophagy; gas therapy; nanozyme; tetrapod

DOI:  https://doi.org/10.1021/acsnano.2c03422
Adv Mater. 2022 Oct 14. e2207961

Photothermal Nanozyme-based Microneedle Patch against Refractory Bacterial Biofilm Infection via Iron-actuated Janus Ion Therapy.

Wanbo Zhu, Jiawei Mei, Xianzuo Zhang, Jun Zhou, Dongdong Xu, Zheng Su, Shiyuan Fang, Jiaxing Wang, Xianlong Zhang, Chen Zhu.

  Owing to high antibiotic resistance and thermotolerance, bacterial biofilm infections (BBIs) are refractory to elimination. Iron is essential for bacterial growth and metabolism, and bacteria can thus accumulate iron from surrounding cells to maintain biofilm formation and survival. Consequently, iron deficiency in the biofilm microenvironment (BME) leads to the functional failure of innate immune cells. Herein, a novel antibiofilm strategy of iron-actuated Janus ion therapy (IJIT) is proposed to regulate iron metabolism in both bacterial biofilm and immune cells. A BME-responsive photothermal microneedle patch (FGO@MN) is synthesized by the growth of Fe3O4 nanoparticles on graphene oxide nanosheets and then encapsulated in methacrylated hyaluronic acid needle tips. The catalytic product of ·OH by FGO@MN in BME disrupts the bacterial heat-shock proteins, coercing biofilm thermal sensitization. As synergistic mild photothermal treatment (mPTT) triggers iron uptake, the intracellular iron overload further induces ferroptosis-like death. Moreover, iron-nourished neutrophils around BME can be rejuvenated for reactivating the suppressed antibiofilm function. Thus, more than 95% BBIs elimination can be achieved by combining heat stress-triggered iron interference with iron-nutrient immune reactivation. Furthermore, in vivo experiments validate the scavenging of refractory BBI after 15 days, suggesting the promising perspective of IJIT in future clinical application. This article is protected by copyright. All rights reserved.

Keywords:  bacterial biofilm infection; ferroptosis; immune regulation; ion therapy; nanozyme-based microneedle patch

DOI:  https://doi.org/10.1002/adma.202207961
Adv Sci (Weinh). 2022 Oct 11. e2203949

Therapeutic Nanocarriers Inhibit Chemotherapy-Induced Breast Cancer Metastasis.

Tianyu Li, Tolulope Akinade, Jie Zhou, Hongxia Wang, Qisong Tong, Siyu He, Emily Rinebold, Luis E Valencia Salazar, Divya Bhansali, Yiling Zhong, Jing Ruan, Jinzhi Du, Piero Dalerba, Kam W Leong.

  Chemotherapy, although effective against primary tumors, may promote metastasis by causing the release of proinflammatory factors from damaged cells. Here, polymeric nanoparticles that deliver chemotherapeutics and scavenge proinflammatory factors simultaneously to inhibit chemotherapy-induced breast cancer metastasis are developed. The cationic nanoparticles can adsorb cell-free nucleic acids (cfNAs) based on charge-charge interaction, which downregulates the expression of Toll-like receptors and then reduces the secretion of inflammatory cytokines. Through in vitro structural optimization, cationic polyamidoamine (PAMAM) dendrimers modified with drug-binding dodecyl groups and diethylethanolamine surface groups (PAMAM-G3-C125 -DEEA20 ) exhibit the most desirable combination of nanoparticle size (≈140 nm), drug loading, cytotoxicity, cfNA binding, and anti-inflammatory activity. In the mouse models of breast cancer metastasis, paclitaxel-loaded nanoparticles reduce serum levels of cfNAs and inflammatory cytokines compared with paclitaxel treatment alone and inhibit both primary tumor growth and tumor metastasis. Additionally, no significant side effects are detected in the serum or major organs. These results provide a strategy to deliver chemotherapeutics to primary tumors while reducing the prometastatic effects of chemotherapy.

Keywords:  breast cancer; cell-free nucleic acid; chemotherapy; metastasis; nanocarrier; scavenger

DOI:  https://doi.org/10.1002/advs.202203949
Nat Commun. 2022 Oct 11. 13(1): 5998

Monobody adapter for functional antibody display on nanoparticles for adaptable targeted delivery applications.

C Albert, L Bracaglia, A Koide, J DiRito, T Lysyy, L Harkins, C Edwards, O Richfield, J Grundler, K Zhou, E Denbaum, G Ketavarapu, T Hattori, S Perincheri, J Langford, A Feizi, D Haakinson, S A Hosgood, M L Nicholson, J S Pober, W M Saltzman, S Koide, G T Tietjen.

Vascular endothelial cells (ECs) play a central role in the pathophysiology of many diseases. The use of targeted nanoparticles (NPs) to deliver therapeutics to ECs could dramatically improve efficacy by providing elevated and sustained intracellular drug levels. However, achieving sufficient levels of NP targeting in human settings remains elusive. Here, we overcome this barrier by engineering a monobody adapter that presents antibodies on the NP surface in a manner that fully preserves their antigen-binding function. This system improves targeting efficacy in cultured ECs under flow by >1000-fold over conventional antibody immobilization using amine coupling and enables robust delivery of NPs to the ECs of human kidneys undergoing ex vivo perfusion, a clinical setting used for organ transplant. Our monobody adapter also enables a simple plug-and-play capacity that facilitates the evaluation of a diverse array of targeted NPs. This technology has the potential to simplify and possibly accelerate both the development and clinical translation of EC-targeted nanomedicines.

DOI: https://doi.org/10.1038/s41467-022-33490-8
Nat Commun. 2022 Oct 08. 13(1): 5936

Controllable DNA hybridization by host-guest complexation-mediated ligand invasion.

Lin Xiao, Liang-Liang Wang, Chao-Qun Wu, Han Li, Qiu-Long Zhang, Yang Wang, Liang Xu.

Dynamic regulation of nucleic acid hybridization is fundamental for switchable nanostructures and controllable functionalities of nucleic acids in both material developments and biological regulations. In this work, we report a ligand-invasion pathway to regulate DNA hybridization based on host-guest interactions. We propose a concept of recognition handle as the ligand binding site to disrupt Watson-Crick base pairs and induce the direct dissociation of DNA duplex structures. Taking cucurbit[7]uril as the invading ligand and its guest molecules that are integrated into the nucleobase as recognition handles, we successfully achieve orthogonal and reversible manipulation of DNA duplex dissociation and recovery. Moreover, we further apply this approach of ligand-controlled nucleic acid hybridization for functional regulations of both the RNA-cleaving DNAzyme in test tubes and the antisense oligonucleotide in living cells. This ligand-invasion strategy establishes a general pathway toward dynamic control of nucleic acid structures and functionalities by supramolecular interactions.

DOI: https://doi.org/10.1038/s41467-022-33738-3
Adv Healthc Mater. 2022 Oct 10. e2201585

Enhanced tumor accumulation of multimodal magneto-plasmonic nanoparticles via an implanted micromagnet-assisted delivery strategy.

Sajanlal R Panikkanvalappil, Sharath K Bhagavatula, Kyle Deans, Oliver Jonas, Mohammad Rashidian, Shruti Mishra.

  One of the major shortcomings of nano carriers-assisted cancer therapeutic strategies continues to be the inadequate tumor penetration and retention of systemically administered nanoformulations and its off-target toxicity. Stromal parameters-related heterogeneity in enhanced permeability and retention effect and physicochemical properties of the nanoformulations immensely contributes to their poor tumor extravasation. Herein, we demonstrated a novel tumor targeting strategy, where an intratumorally implanted micromagnet could significantly enhance accumulation of magneto-plasmonic nanoparticles (NPs) at the micromagnet-implanted tumor in bilateral colorectal tumor models while limiting their off-target accumulation. To this end, we developed novel multimodal gold/iron oxide NPs comprised of an array of multifunctional moieties with high therapeutic, sensing, and imaging potential. We also discovered that cancer cell targeted NPs in combination with static magnetic field can selectively induce cancer cell death. A multimodal caspase-3 nanosensor was also developed for real-time visualization of selective induction of apoptosis in cancer cells. In addition, we evaluated the photothermal killing capability of these NPs in vitro and demonstrated their potential for enhanced photothermal ablation in tissue samples. Building on current uses of implantable devices for therapeutic purposes, we envision the proposed micromagnet-assisted NPs delivery approach may be used to accelerate the clinical translation of various nanoformulations. This article is protected by copyright. All rights reserved.

Keywords:  caspase nanosensor; cell death; magneto-plasmonic nanoparticles; micromagnet; tumor targeting

DOI:  https://doi.org/10.1002/adhm.202201585
Adv Healthc Mater. 2022 Oct 13. e2201771

Calcium Hydride-Based Dressing to Promote Wound Healing.

Fei Gong, Nailin Yang, Jiachen Xu, Xiaoyuan Yang, Kailu Wei, Linqian Hou, Bo Liu, He Zhao, Zhuang Liu, Liang Cheng.

  Wound microenvironment with excess reactive oxygen species (ROS) could significantly inhibit wound healing. Encouraged by hydrogen molecules (H2 ) with effective ROS scavenging and calcium hydride (CaH2 ) with sufficient H2 supply, we for the first time employed CaH2 as a therapeutic H2 donor and starch as a diluent to construct CaH2 pulvis dressing for wound healing treatment. We found that CaH2 by generating H2 exhibited excellent ROS scavenging performance, favorable for preserving the oxidative-stress-induced cell death. After being applied onto the skin wound, the CaH2 pulvis dressing with the unique ROS-scavenging ability could accelerate skin wound healing in healthy/diabetic mice (small animal models) and Bama mini-pigs (large animal model). Such CaH2 dressing could release H2 to relieve the inflammation levels, decrease the secretion of pro-inflammatory cytokines, increase the infiltration of inflammation-suppressive immune cells, and promote the regeneration of new blood vessels and collagens, thereby accelerating wound healing. Our work highlighted that the integration of anti-oxidation and anti-inflammation functions based on CaH2 dressing endowed it with a promising possibility for the treatment of inflammatory diseases. This article is protected by copyright. All rights reserved.

Keywords:  CaH2 dressing; ROS-scavenging; anti-inflammation; hydrogen therapy; wound healing

DOI:  https://doi.org/10.1002/adhm.202201771
ACS Nano. 2022 Oct 10.

Porous Silicon-Based Nanomedicine for Simultaneous Management of Joint Inflammation and Bone Erosion in Rheumatoid Arthritis.

Moonkyoung Jeong, Yuna Jung, Junyong Yoon, Jinyoung Kang, Seo Hyeon Lee, Woojin Back, Hyoyeon Kim, Michael J Sailor, Dokyoung Kim, Ji-Ho Park.

  The lack of drugs that target both disease progression and tissue preservation makes it difficult to effectively manage rheumatoid arthritis (RA). Here, we report a porous silicon-based nanomedicine that efficiently delivers an antirheumatic drug to inflamed synovium while degrading into bone-remodeling products. Methotrexate (MTX) is loaded into the porous silicon nanoparticles using a calcium silicate based condenser chemistry. The calcium silicate-porous silicon nanoparticle constructs (pCaSiNPs) degrade and release the drug preferentially in an inflammatory environment. The biodegradation products of the pCaSiNP drug carrier are orthosilicic acid and calcium ions, which exhibit immunomodulatory and antiresorptive effects. In a mouse model of collagen-induced arthritis, systemically administered MTX-loaded pCaSiNPs accumulate in the inflamed joints and ameliorate the progression of RA at both early and established stages of the disease. The disease state readouts show that the combination is more effective than the monotherapies.

Keywords:  bone regeneration; drug delivery; methotrexate; porous silicon nanoparticle; rheumatoid arthritis

DOI:  https://doi.org/10.1021/acsnano.2c04491
Adv Mater. 2022 Oct 12. e2207350

Robust and Multifunctional Kirigami Electronics with Tough and Permeable Aramid Nanofiber Framework.

Hongzhen Liu, Hegeng Li, Zuochen Wang, Xi Wei, Hengjia Zhu, Mingze Sun, Yuan Lin, Lizhi Xu.

  Kirigami designs are advantageous for the construction of wearable electronics due to their high stretchability and conformability on 3D dynamic surfaces of the skin. However, suitable materials technologies that enable robust kirigami devices with desired functionality for skin-interfaces remain limited. Here, a versatile materials platform based on composite nanofiber framework (CNFF) was exploited for the engineering of wearable kirigami electronics. The self-assembled fibrillar network involving aramid nanofibers and polyvinyl alcohol combines high toughness, permeability, and manufacturability, which are desirable for the fabrication of hybrid devices. Multiscale simulations were conducted to explain the high fracture resistance of CNFF-based kirigami structures and provided essential guidance for the design, which can be further generalized to other kirigami devices. Various microelectronic sensors and electroactive polymers were integrated onto CNFF-based materials platform to achieve measurements of electrocardiogram (ECG), electromyogram (EMG), skin temperature, and other physiological parameters. These mechanically robust, multifunctional, lightweight, and biocompatible kirigami devices could shed new insights for the development of advanced wearable systems and human-machine interfaces. This article is protected by copyright. All rights reserved.

Keywords:  fracture resistance; kirigami electronics; nanofiber framework; stretchable electronics; wearable systems

DOI:  https://doi.org/10.1002/adma.202207350
Sci Adv. 2022 Oct 14. 8(41): eabo5224

Pro-inflammatory megakaryocyte gene expression in murine models of breast cancer.

Harvey G Roweth, Michael W Malloy, Gregory J Goreczny, Isabelle C Becker, Qiuchen Guo, Elizabeth A Mittendorf, Joseph E Italiano, Sandra S McAllister, Elisabeth M Battinelli.

Despite abundant research demonstrating that platelets can promote tumor cell metastasis, whether primary tumors affect platelet-producing megakaryocytes remains understudied. In this study, we used a spontaneous murine model of breast cancer to show that tumor burden reduced megakaryocyte number and size and disrupted polyploidization. Single-cell RNA sequencing demonstrated that megakaryocytes from tumor-bearing mice exhibit a pro-inflammatory phenotype, epitomized by increased Ctsg, Lcn2, S100a8, and S100a9 transcripts. Protein S100A8/A9 and lipocalin-2 levels were also increased in platelets, suggesting that tumor-induced alterations to megakaryocytes are passed on to their platelet progeny, which promoted in vitro tumor cell invasion and tumor cell lung colonization to a greater extent than platelets from wild-type animals. Our study is the first to demonstrate breast cancer-induced alterations in megakaryocytes, leading to qualitative changes in platelet content that may feedback to promote tumor metastasis.

DOI: https://doi.org/10.1126/sciadv.abo5224
Nat Commun. 2022 Oct 14. 13(1): 6086

Nanoparticle-based modulation of CD4+ T cell effector and helper functions enhances adoptive immunotherapy.

Ariel Isser, Aliyah B Silver, Hawley C Pruitt, Michal Mass, Emma H Elias, Gohta Aihara, Si-Sim Kang, Niklas Bachmann, Ying-Yu Chen, Elissa K Leonard, Joan G Bieler, Worarat Chaisawangwong, Joseph Choy, Sydney R Shannon, Sharon Gerecht, Jeffrey S Weber, Jamie B Spangler, Jonathan P Schneck.

Helper (CD4+) T cells perform direct therapeutic functions and augment responses of cells such as cytotoxic (CD8+) T cells against a wide variety of diseases and pathogens. Nevertheless, inefficient synthetic technologies for expansion of antigen-specific CD4+ T cells hinders consistency and scalability of CD4+ T cell-based therapies, and complicates mechanistic studies. Here we describe a nanoparticle platform for ex vivo CD4+ T cell culture that mimics antigen presenting cells (APC) through display of major histocompatibility class II (MHC II) molecules. When combined with soluble co-stimulation signals, MHC II artificial APCs (aAPCs) expand cognate murine CD4+ T cells, including rare endogenous subsets, to induce potent effector functions in vitro and in vivo. Moreover, MHC II aAPCs provide help signals that enhance antitumor function of aAPC-activated CD8+ T cells in a mouse tumor model. Lastly, human leukocyte antigen class II-based aAPCs expand rare subsets of functional, antigen-specific human CD4+ T cells. Overall, MHC II aAPCs provide a promising approach for harnessing targeted CD4+ T cell responses.

DOI: https://doi.org/10.1038/s41467-022-33597-y
Sci Adv. 2022 Oct 14. 8(41): eabj1771

Engineering DNA-based synthetic condensates with programmable material properties, compositions, and functionalities.

Sungho Do, Chanseok Lee, Taehyun Lee, Do-Nyun Kim, Yongdae Shin.

Biomolecular condensates participate in diverse cellular processes, ranging from gene regulation to stress survival. Bottom-up engineering of synthetic condensates advances our understanding of the organizing principle of condensates. It also enables the synthesis of artificial systems with novel functions. However, building synthetic condensates with a predictable organization and function remains challenging. Here, we use DNA as a building block to create synthetic condensates that are assembled through phase separation. The programmability of intermolecular interactions between DNA molecules enables the control over various condensate properties including assembly, composition, and function. Similar to the way intracellular condensates are organized, DNA clients are selectively partitioned into cognate condensates. We demonstrate that the synthetic condensates can accelerate DNA strand displacement reactions and logic gate operation by concentrating specific reaction components. We envision that the DNA-based condensates could help the realization of the high-order functions required to build more life-like artificial systems.

DOI: https://doi.org/10.1126/sciadv.abj1771
J Control Release. 2022 Oct 06. pii: S0168-3659(22)00676-9. [Epub ahead of print]

Interplay between mucus mobility and alveolar macrophage targeting of surface-modified liposomes.

Kamila Bohne Japiassu, Francois Fay, Alessandro Marengo, Younès Louaguenouni, Catherine Cailleau, Stéphanie Denis, David Chapron, Nicolas Tsapis, Thais Leite Nascimento, Eliana Martins Lima, Elias Fattal.

  Alveolar macrophages play a crucial role in the initiation and resolution of the immune response in the lungs. Pro-inflammatory M1 alveolar macrophages are an interesting target for treating inflammatory and infectious pulmonary diseases. One commune targeting strategy is to use nanoparticles conjugated with hyaluronic acid, which interact with CD44 overexpressed on the membrane of those cells. Unfortunately, this coating strategy may be countered by the presence on the surface of the nanoparticles of a poly(ethylene glycol) corona employed to improve nanoparticles' diffusion in the lung mucus. This study aims to measure this phenomenon by comparing the behavior in a murine lung inflammation model of three liposomal platforms designed to represent different poly(ethylene glycol) and hyaluronic acid densities (Liposome-PEG, Liposome-PEG-HA and Liposome-HA). In this work, the liposomes were obtained by one-step ethanol injection method. Their interaction with mucin and targeting ability toward pro-inflammatory macrophages were then investigated in vitro and in vivo in a LPS model of lung inflammation. In vitro, poly(ethylene glycol) free HA-liposomes display a superior targeting efficiency toward M1 macrophages, while the addition of poly(ethylene glycol) induces better mucus mobility. Interestingly in vivo studies revealed that the three liposomes showed distinct cell specificity with alveolar macrophages demonstrating an avidity for poly(ethylene glycol) free HA-liposomes, while neutrophils favored PEGylated liposomes exempt of HA. Those results could be explained by the presence of two forces exercising a balance between mucus penetration and receptor targeting. This study corroborates the importance of considering the site of action and the targeted cells when designing nanoparticles to treat lung diseases.

Keywords:  CD44; Hyaluronic acid; Liposome; Lung injury; M1 macrophages; Poly(ethylene glycol)

DOI:  https://doi.org/10.1016/j.jconrel.2022.10.006
Proc Natl Acad Sci U S A. 2022 Oct 18. 119(42): e2206685119

Gluing blood into gel by electrostatic interaction using a water-soluble polymer as an embolic agent.

Zhiping Jin, Hailong Fan, Toshiya Osanai, Takayuki Nonoyama, Takayuki Kurokawa, Hideki Hyodoh, Kotaro Matoba, Akiko Takeuchi, Jian Ping Gong, Miki Fujimura.

  Liquid embolic agents are widely used for the endovascular embolization of vascular conditions. However, embolization based on phase transition is limited by the adhesion of the microcatheter to the embolic agent, use of an organic solvent, unintentional catheter retention, and other complications. By mimicking thrombus formation, a water-soluble polymer that rapidly glues blood into a gel without triggering coagulation was developed. The polymer, which consists of cationic and aromatic residues with adjacent sequences, shows electrostatic adhesion with negatively charged blood substances in a physiological environment, while common polycations cannot. Aqueous polymer solutions are injectable through clinical microcatheters and needles. The formed blood gel neither adhered to the catheter nor blocked the port. Postoperative computed tomography imaging showed that the polymer can block the rat femoral artery in vivo and remain at the injection site without nontarget embolization. This study provides an alternative for the development of waterborne embolic agents.

Keywords:  adjacent sequence; electrostatic interaction; liquid embolic agent

DOI:  https://doi.org/10.1073/pnas.2206685119
ACS Nano. 2022 Oct 14.

Onset of Chirality in Plasmonic Meta-Molecules and Dielectric Coupling.

Kevin Martens, Timon Funck, Eva Y Santiago, Alexander O Govorov, Sven Burger, Tim Liedl.

  Chirality is a fundamental feature in all domains of nature, ranging from particle physics over electromagnetism to chemistry and biology. Chiral objects lack a mirror plane and inversion symmetry and therefore cannot be spatially aligned with their mirrored counterpart, their enantiomer. Both natural molecules and artificial chiral nanostructures can be characterized by their light-matter interaction, which is reflected in circular dichroism (CD). Using DNA origami, we assemble model meta-molecules from multiple plasmonic nanoparticles, representing meta-atoms accurately positioned in space. This allows us to reconstruct piece by piece the impact of varying macromolecular geometries on their surrounding optical near fields. Next to the emergence of CD signatures in the instance that we architect a third dimension, we design and implement sign-flipping signals through addition or removal of single particles in the artificial molecules. Our data and theoretical modeling reveal the hitherto unrecognized phenomenon of chiral plasmonic-dielectric coupling, explaining the intricate electromagnetic interactions within hybrid DNA-based plasmonic nanostructures.

Keywords:  DNA origami; chirality; circular dichroism; meta-molecules; nanoparticles; plasmonics; self-assembly

DOI:  https://doi.org/10.1021/acsnano.2c04729
Adv Mater. 2022 Oct 12. e2207343

Metabolic homeostasis-regulated nanoparticles for antibody-independent cancer radio-immunotherapy.

Wenhao Shen, Teng Liu, Pei Pei, Junmei Li, Sai Yang, Yanxiang Zhang, Hailin Zhou, Lin Hu, Kai Yang.

  The special metabolic traits of cancer cells and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) are promising targets for developing novel cancer therapy strategies, especially the glycolysis and mitochondrial energy metabolism. However, therapies targeting a singular metabolic pathway are always counteracted by the metabolic reprogramming of cancer, resulting in unsatisfactory therapeutic effect. Herein, we employ polyethylene glycol-coated (PEGylated) liposomes as the drug delivery system (DDS) for both mannose and levamisole hydrochloride to simultaneously inhibit glycolysis and restrain mitochondrial energy metabolism and thus inhibit the tumor growth. In combination with radiotherapy, the liposomes could not only modulate the immunosuppressive TME by cellular metabolism regulation to achieve potent therapeutic effect for local tumors, but also suppress the M2 macrophage proliferation triggered by X-ray irradiation and thus enhance the immune response to inhibit metastatic lesions. In brief, we provide a new therapeutic strategy targeting the special metabolic traits of cancer cells and immunosuppressive TAMs to enhance the abscopal effect of radiotherapy for cancer. This article is protected by copyright. All rights reserved.

Keywords:  Abscopal effect; Autophagy; Cell metabolism; Radio-immunotherapy; Tumor-associated macrophages

DOI:  https://doi.org/10.1002/adma.202207343
Proc Natl Acad Sci U S A. 2022 Oct 18. 119(42): e2206563119

Stimuli-responsive vesicles as distributed artificial organelles for bacterial activation.

Ignacio Gispert, James W Hindley, Colin P Pilkington, Hansa Shree, Laura M C Barter, Oscar Ces, Yuval Elani.

  Intercellular communication is a hallmark of living systems. As such, engineering artificial cells that possess this behavior has been at the heart of activities in bottom-up synthetic biology. Communication between artificial and living cells has potential to confer novel capabilities to living organisms that could be exploited in biomedicine and biotechnology. However, most current approaches rely on the exchange of chemical signals that cannot be externally controlled. Here, we report two types of remote-controlled vesicle-based artificial organelles that translate physical inputs into chemical messages that lead to bacterial activation. Upon light or temperature stimulation, artificial cell membranes are activated, releasing signaling molecules that induce protein expression in Escherichia coli. This distributed approach differs from established methods for engineering stimuli-responsive bacteria. Here, artificial cells (as opposed to bacterial cells themselves) are the design unit. Having stimuli-responsive elements compartmentalized in artificial cells has potential applications in therapeutics, tissue engineering, and bioremediation. It will underpin the design of hybrid living/nonliving systems where temporal control over population interactions can be exerted.

Keywords:  artificial cells; artificial organelles; cell signaling; membranes; synthetic biology

DOI:  https://doi.org/10.1073/pnas.2206563119
J Control Release. 2022 Oct 10. pii: S0168-3659(22)00670-8. [Epub ahead of print]351 883-895

A predictive mechanistic model of drug release from surface eroding polymeric nanoparticles.

Rebeca T Stiepel, Erik S Pena, Stephen A Ehrenzeller, Matthew D Gallovic, Liubov M Lifshits, Christopher J Genito, Eric M Bachelder, Kristy M Ainslie.

  Effective drug delivery requires ample dosing at the target tissue while minimizing negative side effects. Drug delivery vehicles such as polymeric nanoparticles (NPs) are often employed to accomplish this challenge. In this work, drug release of numerous drugs from surface eroding polymeric NPs was evaluated in vitro in physiologically relevant pH 5 and neutral buffers. NPs were loaded with paclitaxel, rapamycin, resiquimod, or doxorubicin and made from an FDA approved polyanhydride or from acetalated dextran (Ace-DEX), which has tunable degradation rates based on cyclic acetal coverage (CAC). By varying encapsulate, pH condition, and polymer, a range of distinct drug release profiles were achieved. To model the obtained drug release curves, a mechanistic mathematical model was constructed based on drug diffusion and polymer degradation. The resulting diffusion-erosion model accurately described drug release from the variety of surface eroding NPs. For drug release from varied CAC Ace-DEX NPs, the goodness of fit of the developed diffusion-erosion model was compared to several conventional drug release models. The diffusion-erosion model maintained optimal fit compared to conventional models across a range of conditions. Machine learning was then employed to estimate effective diffusion coefficients for the diffusion-erosion model, resulting in accurate prediction of in vitro release of dexamethasone and 3'3'-cyclic guanosine monophosphate-adenosine monophosphate from Ace-DEX NPs. This predictive modeling has potential to aid in the design of future Ace-DEX formulations where optimized drug release kinetics can lead to a desired therapeutic effect.

Keywords:  Acetalated dextran; Fickian diffusion; Machine learning; Neural network; Polyanhydride; pH responsive

DOI:  https://doi.org/10.1016/j.jconrel.2022.09.067
Nat Commun. 2022 Oct 14. 13(1): 6075

Immunopeptidomics-based design of mRNA vaccine formulations against Listeria monocytogenes.

Rupert L Mayer, Rein Verbeke, Caroline Asselman, Ilke Aernout, Adillah Gul, Denzel Eggermont, Katie Boucher, Fabien Thery, Teresa M Maia, Hans Demol, Ralf Gabriels, Lennart Martens, Christophe Bécavin, Stefaan C De Smedt, Bart Vandekerckhove, Ine Lentacker, Francis Impens.

Listeria monocytogenes is a foodborne intracellular bacterial pathogen leading to human listeriosis. Despite a high mortality rate and increasing antibiotic resistance no clinically approved vaccine against Listeria is available. Attenuated Listeria strains offer protection and are tested as antitumor vaccine vectors, but would benefit from a better knowledge on immunodominant vector antigens. To identify novel antigens, we screen for Listeria peptides presented on the surface of infected human cell lines by mass spectrometry-based immunopeptidomics. In between more than 15,000 human self-peptides, we detect 68 Listeria immunopeptides from 42 different bacterial proteins, including several known antigens. Peptides presented on different cell lines are often derived from the same bacterial surface proteins, classifying these antigens as potential vaccine candidates. Encoding these highly presented antigens in lipid nanoparticle mRNA vaccine formulations results in specific CD8+ T-cell responses and induces protection in vaccination challenge experiments in mice. Our results can serve as a starting point for the development of a clinical mRNA vaccine against Listeria and aid to improve attenuated Listeria vaccines and vectors, demonstrating the power of immunopeptidomics for next-generation bacterial vaccine development.

DOI: https://doi.org/10.1038/s41467-022-33721-y