bims-drudre 2023-01-01 papers

bims-drudre

Biomed News

on Targeted drug delivery and programmed release mechanisms

Issue of 2023–01–01
fiveteen papers selected by
Ceren Kimna, Technical University of Munich

Membrane-fusion-mediated Multiplex Engineering of Tumor Cell Surface Glycans for Enhanced NK Cell Therapy.
Multifunctional 3D-Printed Pollen Grain-Inspired Hydrogel Microrobots for On-Demand Anchoring and Cargo Delivery.
Composite Separable Microneedles for Transdermal Delivery and Controlled Release of Salmon Calcitonin for Osteoporosis Therapy.
Oral Delivery of siRNA Using Fluorinated, Small-Sized Nanocapsules Toward Anti-Inflammation Treatment.
Phase-separated Liposomes Hijack Endogenous Lipoprotein Transport and Metabolism Pathways to Target Subsets of Endothelial Cells in vivo.
Dynamic Transcription Machineries Guide the Synthesis of Temporally Operating DNAzymes, Gated and Cascaded DNAzyme Catalysis.
Genetically engineered probiotics as catalytic glucose depriver for tumor starvation therapy.
A Super Tough, Rapidly Biodegradable Ultrafast Hemostatic Bioglue.
Target-Catalyzed Self-assembly of DNA-Streptavidin Nanogel for Enzyme-free miRNA Assay.
Biomimetic Nanosonosensitizers Combined with Noninvasive Ultrasound Actuation to Reverse Drug Resistance and Sonodynamic-Enhanced Chemotherapy against Orthotopic Glioblastoma.
Ultrasound-Driven Bioadhesive Triboelectric Nanogenerator for Instant Wound Sealing and Electrically Accelerated Healing in Emergencies.
Computational design of CRISPR guide RNAs to enable strain-specific control of microbial consortia.
Trojan Horse Nanocapsule Enabled in Situ Modulation of the Phenotypic Conversion of Th17 Cells to Treg Cells for the Treatment of Multiple Sclerosis in Mice.
Interactions of Inhaled Liposome with Macrophages and Neutrophils Determine Particle Biofate and Anti-Inflammatory Effect in Acute Lung Inflammation.
Extracellular matrix physical properties govern the diffusion of nanoparticles in tumor microenvironment.

Adv Mater. 2022 Dec 24. e2206989

Membrane-fusion-mediated Multiplex Engineering of Tumor Cell Surface Glycans for Enhanced NK Cell Therapy.

Chunxiong Zheng, Qingguo Zhong, Wantong Song, Ke Yi, Huimin Kong, Haixia Wang, Yu Tao, Mingqiang Li, Xuesi Chen.

  Natural killer (NK) cell therapies show potential for tumor treatment but were immunologically resisted by the overexpressed immunosuppressing tumor-cell-surface glycans. To reverse this glycan-mediated immunosuppression, the surface NK-inhibitory glycan expressions need to be downregulated and NK-activating glycan levels should be elevated synchronously with optimal efficiency. Here, we design a core-shell membrane-fusogenic liposome (MFL) to simultaneously achieve the physical modification of NK-activating glycans and biological inhibition of immunosuppressing glycans on the tumor cell surface via a membrane-fusion manner. Loaded into a tumor-microenvironment-triggered-degradable thermosensitive hydrogel, MFLs could be conveniently injected and controllably released into local tumor. Through fusion with tumor cell membrane, the released MFLs could simultaneously deliver sialyltransferase-inhibitor-loaded core into cytoplasm, and anchor NK-activating-glycan-modified shell onto tumor surface. This spatially-differential distribution of core and shell in one cell ensures the effective inhibition of intracellular sialyltransferase to downregulate immunosuppressing sialic acid, and direct presentation of NK-activating Lewis X trisaccharide (LeX) on tumor surface simultaneously. Consequentially, the sialic acid-caused immunosuppression of tumor surface was reprogrammed to be LeX-induced NK activation, resulting in sensitive susceptibility to NK-cell-mediated recognition and lysis for improved tumor elimination. This MFL provides a novel platform for multiplex cell engineering and personalized regulation of intercellular interactions for enhanced cancer immunotherapy. This article is protected by copyright. All rights reserved.

Keywords:  Membrane-fusogenic nanoparticle; cancer therapy; injectable hydrogel; natural killer cell; tumor surface glycan

DOI:  https://doi.org/10.1002/adma.202206989
Adv Mater. 2022 Dec 31. e2209812

Multifunctional 3D-Printed Pollen Grain-Inspired Hydrogel Microrobots for On-Demand Anchoring and Cargo Delivery.

Yun-Woo Lee, Jae-Kang Kim, Ugur Bozuyuk, Nihal Olcay Dogan, Muhammad Turab Ali Khan, Anitha Shiva, Anna-Maria Wild, Metin Sitti.

  While a majority of wireless microrobots has shown multi-responsiveness to implement complex biomedical functions, their functional executions are strongly dependent on the range of stimulus inputs, which curtails their functional diversity. Furthermore, their responsive functions are coupled to each other, which results in the overlap of the task operations. Here, we demonstrate a 3D-printed multifunctional microrobot inspired by pollen grains with three hydrogel components: FePt nanoparticle-embedded PETA, pNIPAM, and pNIPAM-AAc structures. Each of these structures exhibits their respective targeted functions: responding to magnetic fields for torque-driven surface rolling and steering, exhibiting temperature responsiveness for on-demand surface attachment (anchoring), and pH-responsive cargo release. The versatile multifunctional pollen grain-inspired robots conceptualized here pave the way for various future medical microrobots to improve their projected performance and functional diversity. This article is protected by copyright. All rights reserved.

Keywords:  Stimuli-responsive materials; hydrogel microrobot; medical microrobot; multifunctionality; on-demand attachment

DOI:  https://doi.org/10.1002/adma.202209812
ACS Appl Mater Interfaces. 2022 Dec 28.

Composite Separable Microneedles for Transdermal Delivery and Controlled Release of Salmon Calcitonin for Osteoporosis Therapy.

Yao Li, Xiao-Jie Ju, Han Fu, Chang-Hai Zhou, Yi Gao, Jun Wang, Rui Xie, Wei Wang, Zhuang Liu, Liang-Yin Chu.

  A composite separable microneedles (MNs) system consisting of silk fibroin (SF) needle tips and hyaluronic acid (HA) base is developed for transdermal delivery of salmon calcitonin (sCT) for therapy of osteoporosis. Poly(ethylene glycol) (PEG) is used to modulate the conformation structure of SF to achieve controllable sustained release of sCT. The prepared MNs can effectively penetrate the skin stratum corneum. After application to the skin, the HA base is dissolved within 2 min, allowing these SF drug depots to be implanted into the skin for controllable sustained release of sCT. The release kinetics of sCT can be controlled by regulating the conformation of SF with PEG and the interaction between sCT peptide and SF proteins. Compared with traditional needle injection, delivery of sCT using optimized HA-PEG/SF MNs shows better trabecular bone repair for ovariectomized-induced osteoporosis in mice. The proposed MNs system provides a new noninjection strategy for therapy of osteoporosis.

Keywords:  controlled-release kinetics; osteoporosis; salmon calcitonin; separable microneedles; transdermal delivery

DOI:  https://doi.org/10.1021/acsami.2c19241
Adv Mater. 2022 Dec 27. e2206821

Oral Delivery of siRNA Using Fluorinated, Small-Sized Nanocapsules Toward Anti-Inflammation Treatment.

Yuansong Wei, Xudong Li, Juanhui Lin, Yang Zhou, Jiandong Yang, Mengying Hou, Fan Wu, Jin Yan, Chenglong Ge, Duanmin Hu, Lichen Yin.

  Oral delivery of siRNA provides a promising paradigm for treating diseases that require regular injections. However, the multiple gastrointestinal and systemic barriers often lead to inefficient oral absorption and low bioavailability of siRNA. Technologies that can overcome these barriers are still lacking, which hurdles the clinical potential of orally delivered siRNA. Herein, small-sized, fluorinated nanocapsules (F-NCs) were developed to mediate efficient oral delivery of TNF-α siRNA for anti-inflammation treatment. The NCs possessed a disulfide-cross-linked shell structure, thus featuring robust stability in the gastrointestinal tract. Because of their small size (∼30 nm) and fluorocarbon-assisted repelling of mucin adsorption, the best-performing F3 -NCs showed excellent mucus penetration and intestinal transport capabilities without impairing the intestinal tight junction, conferring the oral bioavailability of 20.4% in relative to i.v. injection. The disulfide cross-linker could be cleaved inside target cells, causing NCs dissociation and siRNA release to potentiate the TNF-α silencing efficiency. In murine models of acute and chronic inflammation, orally delivered F3 -NCs provoked efficient TNF-α silencing and pronounced anti-inflammatory efficacies. This study therefore provides a transformative strategy for oral siRNA delivery, and would render promising utilities for anti-inflammation treatment. This article is protected by copyright. All rights reserved.

Keywords:  anti-inflammatory therapy; fluorinated nanocapsules; intestinal absorption; mucus penetration; oral siRNA delivery

DOI:  https://doi.org/10.1002/adma.202206821
Adv Healthc Mater. 2022 Dec 24. e2202709

Phase-separated Liposomes Hijack Endogenous Lipoprotein Transport and Metabolism Pathways to Target Subsets of Endothelial Cells in vivo.

Gabriela Arias-Alpizar, Panagiota Papadopoulou, Xabier Rios, Krishna Reddy Pulagam, Mohammad-Amin Moradi, Roy Pattipeiluhu, Jeroen Bussmann, Nico Sommerdijk, Jordi Llop, Alexander Kros, Frederick Campbell.

  Plasma lipid transport and metabolism is essential to ensure correct cellular function throughout the body. Dynamically regulated in time and space, the well characterized mechanisms underpinning plasma lipid transport and metabolism offer an enticing, but as yet underexplored, rationale to design synthetic lipid nanoparticles with inherent cell/tissue selectivity. Herein, we describe a systemically administered liposome formulation, composed of just two lipids, that is capable of hijacking a triglyceride lipase-mediated lipid transport pathway resulting in liposome recognition and uptake within specific endothelial cell subsets. In the absence of targeting ligands, liposome-lipase interactions are mediated by a unique, phase-separated ("parachute") liposome morphology. Within the embryonic zebrafish, selective liposome accumulation is observed at the developing blood-brain-barrier. In mice, extensive liposome accumulation within the liver and spleen - which is reduced but not eliminated following small molecule lipase inhibition - supports a role for endothelial lipase but highlights these liposomes are also subject to significant "off-target" by reticuloendothelial system organs. Overall, these compositionally simplistic liposomes offer new insights into the discovery and design of lipid-based nanoparticles that can exploit endogenous lipid transport and metabolism pathways to achieve cell selective targeting in vivo. This article is protected by copyright. All rights reserved.

Keywords:  lipases; lipid nanoparticles; liposomes; nanomedicine; phase-separated; zebrafish

DOI:  https://doi.org/10.1002/adhm.202202709
ACS Nano. 2022 Dec 28.

Dynamic Transcription Machineries Guide the Synthesis of Temporally Operating DNAzymes, Gated and Cascaded DNAzyme Catalysis.

Jiantong Dong, Itamar Willner.

  Transient transcription machineries play important roles in the dynamic modulation of gene expression and the sequestered regulation of cellular networks. The present study emulates such processes by designing artificial reaction modules consisting of transcription machineries that guide the transient synthesis of catalytic DNAzymes, the transient operation of gated DNAzymes, and the temporal activation of an intercommunicated DNAzyme cascade. The reaction modules rely on functional constituents that lead to the triggered activation of transcription machineries in the presence of the nucleoside triphosphates oligonucleotide fuel, yielding the transient formation and dissipative depletion of the intermediate DNAzyme(s) products. The kinetics of the transient DNAzyme networks are computationally simulated, allowing to predict and experimentally validate the performance of the systems under different auxiliary conditions. The study advances the field of systems chemistry by introducing transcription machinery-based networks for the dynamic control over transient catalysis─a primary step toward life-like cellular assemblies.

Keywords:  DNA nanotechnology; RNA; RNase; kinetic simulation; network; out-of-equilibrium; systems chemistry

DOI:  https://doi.org/10.1021/acsnano.2c10108
Mater Today Bio. 2023 Feb;18 100515

Genetically engineered probiotics as catalytic glucose depriver for tumor starvation therapy.

Penghao Ji, Bolin An, Zhongming Jie, Liping Wang, Shuwen Qiu, Changhao Ge, Qihui Wu, Jianlin Shi, Minfeng Huo.

  Cancer cells predominantly adapt the frequent but less efficient glycolytic process to produce ATPs rather than the highly efficient oxidative phosphorylation pathway. Such a regulated metabolic pattern in cancer cells offers promising therapeutic opportunities to kill tumors by glucose depletion or glycolysis blockade. In addition, to guarantee tumor-specific therapeutic targets, effective tumor-homing, accumulation, and retention strategies toward tumor regions should be elaborately designed. In the present work, genetically engineered tumor-targeting microbes (transgenic microorganism EcM-GDH (Escherichia coli MG1655) expressing exogenous glucose dehydrogenase (GDH) have been constructed to competitively deprive tumors of glucose nutrition for metabolic intervention and starvation therapy. Our results show that the engineered EcM-GDH can effectively deplete glucose and trigger pro-death autophagy and p53-initiated apoptosis in colorectal tumor cells/tissues both in vitro and in vivo. The present design illuminates the promising prospects for genetically engineered microbes in metabolic intervention therapeutics against malignant tumors based on catalytically nutrient deprivation, establishing an attractive probiotic therapeutic strategy with high effectiveness and biocompatibility.

Keywords:  Autophagy; Glucose deprivation; Metabolic intervention; Programmable living biomaterials; Tumor targeting

DOI:  https://doi.org/10.1016/j.mtbio.2022.100515
Adv Mater. 2022 Dec 29. e2208622

A Super Tough, Rapidly Biodegradable Ultrafast Hemostatic Bioglue.

Hufei Wang, Junyao Cheng, Feifei Sun, Xueyu Dou, Jianheng Liu, Yiru Wang, Ming Li, Jianpeng Gao, Xiao Liu, Xing Wang, Fei Yang, Ziran Zhu, Hong Shen, Licheng Zhang, Peifu Tang, Decheng Wu.

  Death happening in massive hemorrhage has been involved in military conflicts, traffic accidents, and surgical injuries of various human disasters. Achieving rapid and effective hemostasis to save lives is crucial in urgent massive bleeding situations. Herein, we develop a covalent crosslinked AG-PEG glue based on extracellular matrix-like amino-gelatin (AG) and PEG derivatives. The AG-PEG glue gelatinizes fast and exhibits firm and indiscriminate close adhesion with various moist tissues upon being dosed. The formed glue establishes an adhesive and robust barrier to seal the arterial, hepatic and cardiac hemorrhagic wounds, enabling it to withstand up to 380 mmHg blood pressure in comparison with normal systolic blood pressure of 60-180 mmHg. Remarkably, massive bleeding from a pig cardiac penetrating hole with 6 mm diameter is effectively stopped using the glue within 60 seconds. Postoperative indexes of the treated pig gradually recover and the cardiac wounds regrow significantly at 14 days. Possessing on-demand solubility, self-gelling and rapid degradability, the AG-PEG glue may provide a fascinating stop bleeding approach for clinical hemostasis and emergency rescue. This article is protected by copyright. All rights reserved.

Keywords:  bioadhesive; biodegradable bioglue; hemostasis; sealant; tough hydrogel

DOI:  https://doi.org/10.1002/adma.202208622
Adv Healthc Mater. 2022 Dec 29. e2202076

Target-Catalyzed Self-assembly of DNA-Streptavidin Nanogel for Enzyme-free miRNA Assay.

Jae Chul Park, Hyebin Na, Saehan Choi, Huiju Jeon, Yoon Sung Nam.

  Rapid, sensitive, specific, and user-friendly microRNA (miRNA) assay is highly demanded for point-of-care diagnosis. Target-catalyzed toehold-mediated strand displacement (TMSD) has received increasing attention as an enzyme-free molecular tool for DNA detection. However, the application of TMSD to miRNA targets is challenging because relatively weak DNA/RNA hybridization leads to failure in the subtle kinetic control of multiple hybridization steps. Here, we present a simple method for miRNA assay based on the one-pot self-assembly of Y-shaped DNAs with streptavidin via a miRNA-catalyzed TMSD cascade reaction. A single miRNA catalyzes the opening cycle of DNA hairpin loops to generate multiple Y-shaped DNAs carrying biotin and a quencher at the end of their arms. Introducing a single base-pair mismatch near the toehold facilitates RNA-triggered strand displacement while barely disturbing non-specific reactions. The Y-shaped DNAs are self-assembled with fluorescently labeled streptavidin (sAv), which produces nanoscale DNA-sAv nanogel particles mediating efficient Förster resonance energy transfer in their three-dimensional network. The enhancing effect dramatically reduces the detection limit from the nanomolar level to the picomolar level. This work proves that TMSD-based DNA nanogel with a base-pair mismatch incorporated to a hairpin structure is a promising approach towards sensitive and accurate miRNA assay. This article is protected by copyright. All rights reserved.

Keywords:  Base-pair mismatch; Förster resonance energy transfer; microRNA assay; nanogel; toehold-mediated strand displacement

DOI:  https://doi.org/10.1002/adhm.202202076
ACS Nano. 2022 Dec 27.

Biomimetic Nanosonosensitizers Combined with Noninvasive Ultrasound Actuation to Reverse Drug Resistance and Sonodynamic-Enhanced Chemotherapy against Orthotopic Glioblastoma.

Huaqing Chen, Shengping Zhang, Quan Fang, Huamei He, Jian Ren, Da Sun, Jiazheng Lai, Aiqing Ma, Ze Chen, Lanlan Liu, Ruijing Liang, Lintao Cai.

  Glioblastoma (GBM) is the most devastating brain tumor and highly resistant to conventional chemotherapy. Herein, we introduce biomimetic nanosonosensitizer systems (MDNPs) combined with noninvasive ultrasound (US) actuation for orthotopic GBM-targeted delivery and sonodynamic-enhanced chemotherapy. MDNPs were fabricated with biodegradable and pH-sensitive polyglutamic acid (PGA) and the chemotherapeutic agent and sonosensitizer doxorubicin (DOX), camouflaged with human GBM U87 cell membranes. MDNPs presented homologous targeting accumulation and in vivo long-term circulation ability. They effectively passed through the blood-brain barrier (BBB) under US assistance and reached the orthotopic GBM site. MDNPs exhibited controllable US-elicited sonodynamic effect by generation of reactive oxygen species (ROS). ROS not only induced cancer cell apoptosis but also downregulated drug-resistance-related factors to disrupt chemoresistance and increase sensitivity to chemotherapy. The in vivo study of orthotopic GBM treatments further proved that MDNPs exhibited US-augmented synergistic antitumor efficacy and strongly prolonged the survival rate of mice. The use of low-dose DOX and the safety of US enabled repeated treatment (4 times) without obvious cardiotoxicity. This effective and safe US-enhanced chemotherapy strategy with the advantages of noninvasive brain delivery and high drug sensitivity holds great promise for deep-seated and drug-resistant tumors.

Keywords:  chemoresistance; glioblastoma; nanosonosensitizer; sonodynamic effect; ultrasound

DOI:  https://doi.org/10.1021/acsnano.2c08861
Adv Mater. 2022 Dec 27. e2209054

Ultrasound-Driven Bioadhesive Triboelectric Nanogenerator for Instant Wound Sealing and Electrically Accelerated Healing in Emergencies.

Xiangchun Meng, Xiao Xiao, Sera Jeon, Dabin Kim, Byung-Joon Park, Young-Jun Kim, Najaf Rubab, SeongMin Kim, Sang-Woo Kim.

  In this work, we design a bioadhesive triboelectric nanogenerator (BA-TENG) as a first-aid rescue for instant and robust wound sealing, and ultrasound-driven accelerated wound healing. This BA-TENG is fabricated with biocompatible materials, and integrates a flexible TENG as the top layer and bioadhesive as the bottom layer, resulting in effective electricity supply and strong sutureless sealing capability on wet tissues. When driven by ultrasound, BA-TENG can produce stable voltage of 1.50 V and current of 24.20 μA underwater. The ex vivo porcine colon organ models showed that BA-TENG sealed defects instantly (∼ 5 s) with high interfacial toughness (∼ 150 J m-2 ), while the rat bleeding liver incision model confirmed that BA-TENG performed rapid wound closure and hemostasis, reducing the blood loss by 82%. When applied in living rats, BA-TENG not only sealed skin injuries immediately but also produced a strong electric field (E-field) of about 0.86 kV m-1 stimulated by ultrasound to accelerate skin wound healing significantly. The in vitro studies confirmed that these effects were attributed to the E-field-accelerated cell migration and proliferation. In addition, these TENG adhesives could be applied to not only wound treatment, nerve stimulation and regeneration, and charging batteries in implanted devices. This article is protected by copyright. All rights reserved.

Keywords:  bioadhesive; triboelectric nanogenerator; ultrasound; wound healing; wound sealing

DOI:  https://doi.org/10.1002/adma.202209054
Proc Natl Acad Sci U S A. 2023 Jan 03. 120(1): e2213154120

Computational design of CRISPR guide RNAs to enable strain-specific control of microbial consortia.

Austin G Rottinghaus, Steven Vo, Tae Seok Moon.

  Microbes naturally coexist in complex, multistrain communities. However, extracting individual microbes from and specifically manipulating the composition of these consortia remain challenging. The sequence-specific nature of CRISPR guide RNAs can be leveraged to accurately differentiate microorganisms and facilitate the creation of tools that can achieve these tasks. We developed a computational program, ssCRISPR, which designs strain-specific CRISPR guide RNA sequences with user-specified target strains, protected strains, and guide RNA properties. We experimentally verify the accuracy of the strain specificity predictions in both Escherichia coli and Pseudomonas spp. and show that up to three nucleotide mismatches are often required to ensure perfect specificity. To demonstrate the functionality of ssCRISPR, we apply computationally designed CRISPR-Cas9 guide RNAs to two applications: the purification of specific microbes through one- and two-plasmid transformation workflows and the targeted removal of specific microbes using DNA-loaded liposomes. For strain purification, we utilize gRNAs designed to target and kill all microbes in a consortium except the specific microbe to be isolated. For strain elimination, we utilize gRNAs designed to target only the unwanted microbe while protecting all other strains in the community. ssCRISPR will be of use in diverse microbiota engineering applications.

Keywords:  computational CRISPR RNA design; liposome-mediated delivery; microbial consortium engineering; targeted microbial killing; targeted strain isolation from microbiota

DOI:  https://doi.org/10.1073/pnas.2213154120
Adv Mater. 2022 Dec 27. e2210262

Trojan Horse Nanocapsule Enabled in Situ Modulation of the Phenotypic Conversion of Th17 Cells to Treg Cells for the Treatment of Multiple Sclerosis in Mice.

Chongdeng Shi, Jing Zhang, Huijun Wang, Chen Chen, Maosen Han, Lin Gao, Chunwei Tang, Peng Sun, Xiaotian Zhao, Feiyue Guo, Zhaozhong Wang, Mohnad Abdalla, Zhenmei Yang, Ying Liu, Anning Li, Cai Zhang, Xinyi Jiang.

  Th17/Treg imbalance is closely related to the occurrence and development of multiple sclerosis (MS), and the transdifferentiation of Th17 cells into Treg cells may contribute to the resolution of inflammation, presenting a therapeutic strategy for MS. To modulate this phenotypic shift in situ, we report a "Trojan horse"-like hybrid system, nanocapsule-coupled Th17 cells, for MS treatment. Following intravenous injection into MS mice, the hybrid system efficiently transmigrated across the blood-brain barrier (BBB) and homed to the inflamed MS niche. Aminooxy-acetic acid (AOA), a transdifferentiation inducer, was locally released upon the production of ROS and in turn taken up by Th17 cells. We demonstrated that the Trojan horse hybrid system enabled in situ phenotypic transdifferentiation of Th17 cells into anti-inflammatory Treg cells. This phenotypic conversion led to a domino-like immune response that was conducive to MS therapy. Overall, this work highlights a new pathway for accurate modulation of the phenotypes of adoptively transferred cells in situ, from proinflammatory to anti-inflammatory for MS therapy, and may be broadly applicable for patients suffering from other autoimmune diseases. This article is protected by copyright. All rights reserved.

Keywords:  CNS inflammation; Th17 cells; Treg cells; cellular combination delivery system; drug delivery; multiple sclerosis

DOI:  https://doi.org/10.1002/adma.202210262
ACS Appl Mater Interfaces. 2022 Dec 30.

Interactions of Inhaled Liposome with Macrophages and Neutrophils Determine Particle Biofate and Anti-Inflammatory Effect in Acute Lung Inflammation.

Chang Liu, Yihan Liu, Long Xi, Yuan He, Yingmin Liang, Judith Choi Wo Mak, Shirui Mao, Zhenping Wang, Ying Zheng.

  Since most current studies have focused on exploring how phagocyte internalization of drug-loaded nanovesicles by macrophages would affect the function and therapeutic effects of infiltrated neutrophils or monocytes, research has evaluated the specificity of the inhaled nanovesicles for targeting various phagocytes subpopulations. In this study, liposomes with various charges (including neutral (L1), anionic (L2), and cationic at inflammatory sites (L3)) were constructed to investigate how particle charge determined their interactions with key phagocytes (including macrophages and neutrophils) in acute lung injury (ALI) models and to establish correlations with their biofate and overall anti-inflammatory effect. Our results clearly indicated that neutrophils were capable of rapidly sequestering L3 with a 3.2-fold increase in the cellular liposome distribution, compared to that in AMs, while 70.5% of L2 were preferentially uptaken by alveolar macrophages (AMs). Furthermore, both AMs and the infiltrated neutrophils performed as the potential vesicles for the inhaled liposomes to prolong their lung retention in ALI models, whereas AMs function as sweepers to recognize and process liposomes in the healthy lung. Finally, inhaled roflumilast-loaded macrophage or neutrophil preferential liposomes (L2 or L3) exhibited optimal anti-inflammatory effect because of the decreased AMs phagocytic capacity or the prolonged circulation times of neutrophils. Such findings will be beneficial in exploiting a potential pathway to specifically manipulate lung phagocyte functions in lung inflammatory diseases where these cells play crucial roles.

Keywords:  acute lung inflammation; bio−nano interaction; inhaled liposome; lung phagocytes; lung retention

DOI:  https://doi.org/10.1021/acsami.2c17660
Proc Natl Acad Sci U S A. 2023 Jan 03. 120(1): e2209260120

Extracellular matrix physical properties govern the diffusion of nanoparticles in tumor microenvironment.

Xiaocong He, Yuanyuan Yang, Yulong Han, Chunyu Cao, Zhongbin Zhang, Lingxiao Li, Cailan Xiao, Hui Guo, Lin Wang, Lichun Han, Zhiguo Qu, Na Liu, Shuang Han, Feng Xu.

  Nanoparticles (NPs) are confronted with limited and disappointing delivery efficiency in tumors clinically. The tumor extracellular matrix (ECM), whose physical traits have recently been recognized as new hallmarks of cancer, forms a main steric obstacle for NP diffusion, yet the role of tumor ECM physical traits in NP diffusion remains largely unexplored. Here, we characterized the physical properties of clinical gastric tumor samples and observed limited distribution of NPs in decellularized tumor tissues. We also performed molecular dynamics simulations and in vitro hydrogel experiments through single-particle tracking to investigate the diffusion mechanism of NPs and understand the influence of tumor ECM physical properties on NP diffusion both individually and collectively. Furthermore, we developed an estimation matrix model with evaluation scores of NP diffusion efficiency through comprehensive analyses of the data. Thus, beyond finding that loose and soft ECM with aligned structure contribute to efficient diffusion, we now have a systemic model to predict NP diffusion efficiency based on ECM physical traits and provide critical guidance for personalized tumor diagnosis and treatment.

Keywords:  nanoparticle diffusion; physical microenvironment; tumor extracellular matrix

DOI:  https://doi.org/10.1073/pnas.2209260120