bims-drudre 2022-12-11 papers

bims-drudre

Biomed News

on Targeted drug delivery and programmed release mechanisms

Issue of 2022‒12‒11
eighteen papers selected by
Ceren Kimna
Technical University of Munich

Unraveling Plasma Protein Corona by Ultrasonic Cavitation Augments Active-Transporting of Liposome in Solid Tumor.
m6 A Reader YTHDF1-targeting Engineered Small Extracellular Vesicles for Gastric Cancer Therapy Via Epigenetic and Immune Regulation.
Thermoresponsive Self-Healing Zwitterionic Hydrogel as an In Situ Gelling Wound Dressing for Rapid Wound Healing.
Targeting Cell Membranes, Depleting ROS by Dithiane and Thioketal-Containing Polymers with Pendant Cholesterols Delivering Necrostatin-1 for Glaucoma Treatment.
Toehold clipping: A mechanism for remote control of DNA strand displacement.
Programming DNA Aptamer Arrays of Prescribed Spatial Features with Enhanced Bioavailability and Cell Growth Modulation.
Tetrahedral DNA Nanostructure with Interferon Stimulatory DNA Delivers Highly Potent Toxins Activates the cGAS-STING Pathway for Robust Chemotherapy and Immunotherapy.
Self-assembling nanofibrous bacteriophage microgels as sprayable antimicrobials targeting multidrug-resistant bacteria.
Venation-Mimicking, Ultra-Stretchable, Room Temperature-Attachable Metal Tapes for Integrated Electronic Skins.
A library of base editors for the precise ablation of all protein-coding genes in the mouse mitochondrial genome.
Closed-loop chemical recycling of cross-linked polymeric materials based on reversible amidation chemistry.
Fast and Dynamic Mapping of the Protein Corona on Nanoparticle Surfaces by Photocatalytic Proximity Labeling.
Engineered Lactococcus lactis secreting Flt3L and OX40 ligand for in situ vaccination-based cancer immunotherapy.
Efficient Tumor Eradication at Ultralow Drug Concentration via Externally Controlled and Boosted Metallic Iron Magnetoplasmonic Nanocapsules.
Suppressing the dynamic oxygen evolution of sodium layered cathodes through synergistic surface dielectric polarization and bulk site-Selective Co-doping.
A nanosystem modulates immunosuppressive tumor microenvironment metabolism to amplify immunotherapy.
Evaluation in pig of an intestinal administration device for oral peptide delivery.
Enhanced immune responses to vaccine antigens in the corneal stroma.

Adv Mater. 2022 Dec 07. e2207271

Unraveling Plasma Protein Corona by Ultrasonic Cavitation Augments Active-Transporting of Liposome in Solid Tumor.

Guowei Wang, Yifan Jiang, Junjun Xu, Jiaxin Shen, Tao Lin, Jifan Chen, Weidong Fei, Yating Qin, Zhuxian Zhou, Youqing Shen, Pintong Huang.

  Ligand/receptor-mediated targeted drug delivery has been widely recognized as a promising strategy for improving nanomedicines' clinical efficacy but was attenuated by the binding of plasma protein on the surface of nanoparticles to form protein corona. Here, we show that ultrasonic cavitation can be used to unravel surface plasma coronas on liposomal nanoparticles through ultrasound (US)-induced liposomal reassembly. To demonstrate the feasibility and effectiveness of the method, we developed transcytosis-targeting peptide decorated reconfigurable liposomes (LPGL) loaded with gemcitabine (GEM) and perfluoropentane (PFP) for cancer-targeted therapy. In the blood circulation, the targeting peptides were deactivated by plasma corona and lost their targeting capability. Once they reached tumor blood vessels, the US irradiation induced transformation of LPGL from nanodrops into microbubble via liquid-gas phase transition and decorticated surface corona by reassembly of the lipid membrane. The activated liposomes regained the capability to recognize the receptors on tumor neovascularization, initiated ligand/receptor-mediated transcytosis, achieved efficient tumor accumulation and penetration, and led to potent antitumor activity in multiple tumor models of patient-derived tumor xenograft. This study presents an effective strategy to tackle the fluid biological barriers of protein corona and develop transcytosis-targeting liposomes for active tumor transport and efficient cancer therapy. This article is protected by copyright. All rights reserved.

Keywords:  active tumor targeting; liposome; protein corona; transcytosis; ultrasonic cavitation

DOI:  https://doi.org/10.1002/adma.202207271
Adv Mater. 2022 Dec 09. e2204910

m6 A Reader YTHDF1-targeting Engineered Small Extracellular Vesicles for Gastric Cancer Therapy Via Epigenetic and Immune Regulation.

Qing You, Fang Wang, Rong Du, Jingnan Pi, Huayi Wang, Yue Huo, Jingyi Liu, Chen Wang, Jia Yu, Yanlian Yang, Ling Zhu.

  N6 -methyladenosine (m6 A) modulators decide the fate of m6 A-modified transcripts and drive cancer development. RNA interference targeting m6 A modulators promises to be an emerging cancer therapy but is challenging due to its poor tumor targeting and high systematic toxicity. Here we develop engineered small extracellular vesicles (sEVs) with high CD47 expression and cyclic arginine-glycine-aspartic (c(RGDyC)) modification for effective delivery of short interfering RNA (siRNA) against m6 A reader YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) to treat gastric cancer via epigenetic and immune regulation. This nanosystem efficiently depletes YTHDF1 expression and suppresses gastric cancer progression and metastasis through hampering frizzled7 (FZD7) translation and inactivating Wnt/β-catenin pathway in an m6 A dependent manner. Loss of YTHDF1 mediates overexpression of interferon (IFN)-γ receptor 1 (IFNGR1) and enhances IFN-γ response, promoting expression of major histocompatibility complex class I (MHC-I) on tumor cells to achieve self-presentation of the immunogenic tumor cells to stimulate strong cytotoxic T lymphocytes (CTL) responses. CD47 expression on the engineered sEVs can competitively bind with signal regulatory protein α (SIRPα) to enhance phagocytosis of the tumor cells by tumor associated macrophages (TAMs). This versatile nanoplatform provides an efficient and low toxic strategy to inhibit epigenetic regulators and holds great potential in promoting immunotherapy. This article is protected by copyright. All rights reserved.

Keywords:  YTHDF1; extracellular vesicle; gastric cancer; immune regulation; m6A modulator; siRNA delivery

DOI:  https://doi.org/10.1002/adma.202204910
ACS Appl Mater Interfaces. 2022 Dec 06.

Thermoresponsive Self-Healing Zwitterionic Hydrogel as an In Situ Gelling Wound Dressing for Rapid Wound Healing.

Ye Wang, Changyuan He, Chong Chen, Wentao Dong, Xuekun Yang, Ye Wu, Qingquan Kong, Bin Yan.

  It is highly desired yet challenging to fabricate biocompatible injectable self-healing hydrogels with anti-bacterial adhesion properties for complex wounds that can autonomously adapt to different shapes and depths and can promote angiogenesis and dermal collagen synthesis for rapid wound healing. Herein, an injectable zwitterionic hydrogel with excellent self-healing property, good cytocompatibility, and antibacterial adhesion was developed from a thermoresponsive ABA triblock copolymer poly[(N-isopropyl acrylamide)-co-(butyl acrylate)-co-(sulfobetaine methacrylate)]-b-poly(ethylene glycol)-b-poly[(N-isopropyl acrylamide)-co-(butyl acrylate)-co-(sulfobetaine methacrylate)] (PZOPZ). The prepared PZOPZ hydrogel exhibits a distinct thermal-induced sol-gel transition around physiological temperature and could be easily applied in a sol state and in situ gelled to adapt complex wounds of different shapes and depths for complete coverage. Meanwhile, the hydrogel possesses a rapid self-healing ability and can recover autonomously from damage to maintain structural and functional integrity. In addition, the CCK-8 and 2D/3D cell culture experiments revealed that the PZOPZ hydrogel dressing shows low cytotoxicity to L929 cells and can effectively prevent the adhesion of Staphylococcus aureus and Escherichia coli. In vivo investigations verified that the PZOPZ hydrogel could increase angiogenesis and dermal collagen synthesis and shorten the transition from the inflammatory to the proliferative stage, thereby providing more favorable conditions for faster wound healing. Overall, this work provides a promising strategy to develop injectable zwitterionic hydrogel dressings with multiple functions for clinic wound management.

Keywords:  anti-bacterial adhesion; injectable hydrogels; self-healing hydrogel; wound dressing; zwitterionic hydrogel

DOI:  https://doi.org/10.1021/acsami.2c15820
ACS Nano. 2022 Dec 09.

Targeting Cell Membranes, Depleting ROS by Dithiane and Thioketal-Containing Polymers with Pendant Cholesterols Delivering Necrostatin-1 for Glaucoma Treatment.

Rong Rong, Xuezhi Zhou, Ganghao Liang, Haibo Li, Mengling You, Zhuotao Liang, Zhou Zeng, Haihua Xiao, Dan Ji, Xiaobo Xia.

  Glaucoma is the leading cause of irreversible blindness worldwide, characterized by progressive vision loss due to the selective damage to retinal ganglion cells (RGCs) and their axons. Oxidative stress is generally believed as one key factor of RGCs death. Recently, necroptosis was identified to play a key role in glaucomatous injury. Therefore, depletion of reactive oxygen species (ROS) and inhibition of necroptosis in RGCs has become one of treatment strategies for glaucoma. However, existing drugs without efficient drug enter into the retina and have controlled release due to a short drug retention. Herein, we designed a glaucomatous microenvironment-responsive drug carrier polymer, which is characterized by the presence of thioketal bonds and 1,4-dithiane unit in the main chain for depleting ROS as well as the pendant cholesterols for targeting cell membranes. This polymer was adopted to encapsulate an inhibitor of necroptosis, necrostatin-1, into nanoparticles (designated as NP1). NP1 with superior biosafety could scavenge ROS in RGCs both in vitro and in vivo of an acute pathological glaucomatous injury model. Further, NP1 was found to effectively inhibit the upregulation of the necroptosis pathway, reducing the death of RGCs. The findings in this study exemplified the use of nanomaterials as potential strategies to treat glaucoma.

Keywords:  glaucoma; nanoparticle; necroptosis; reactive oxygen species; retinal ganglion cell

DOI:  https://doi.org/10.1021/acsnano.2c09202
Nucleic Acids Res. 2022 Dec 08. pii: gkac1152. [Epub ahead of print]

Toehold clipping: A mechanism for remote control of DNA strand displacement.

Hiba Faheem, Johnsi Mathivanan, Hannah Talbot, Hana Zeghal, Sweta Vangaveti, Jia Sheng, Alan A Chen, Arun Richard Chandrasekaran.

The ability to create stimuli-responsive DNA nanostructures has played a prominent role in dynamic DNA nanotechnology. Primary among these is the process of toehold-based strand displacement, where a nucleic acid molecule can act as a trigger to cause conformational changes in custom-designed DNA nanostructures. Here, we add another layer of control to strand displacement reactions through a 'toehold clipping' process. By designing DNA complexes with a photocleavable linker-containing toehold or an RNA toehold, we show that we can use light (UV) or enzyme (ribonuclease) to eliminate the toehold, thus preventing strand displacement reactions. We use molecular dynamics simulations to analyze the structural effects of incorporating a photocleavable linker in DNA complexes. Beyond simple DNA duplexes, we also demonstrate the toehold clipping process in a model DNA nanostructure, by designing a toehold containing double-bundle DNA tetrahedron that disassembles when an invading strand is added, but stays intact after the toehold clipping process even in the presence of the invading strand. This work is an example of combining multiple physical or molecular stimuli to provide additional remote control over DNA nanostructure reconfiguration, advances that hold potential use in biosensing, drug delivery or molecular computation.

DOI: https://doi.org/10.1093/nar/gkac1152
Nano Lett. 2022 Dec 08.

Programming DNA Aptamer Arrays of Prescribed Spatial Features with Enhanced Bioavailability and Cell Growth Modulation.

Fan Xu, Qing Xia, Jing Ye, Liang Dong, Donglei Yang, Wei Xue, Pengfei Wang.

  Epithelial cell adhesion molecules (EpCAMs) play pivotal roles in tumorigenesis in many cancer types, which is reported to reside within nano- to microscale membrane domains, forming small clusters. We propose that building multivalent ligands that spatially patch to EpCAM clusters may largely enhance their targeting capability. Herein, we assembled EpCAM aptamers into nanoscale arrays of prescribed valency and spatial arrangements by using a rectangular DNA pegboard. Our results revealed that EpCAM aptamer arrays exhibited significantly higher binding avidity to MCF-7 cells than free monovalent aptamers, which was affected by both valency and spatial arrangement of aptamers. Furthermore, EpCAM aptamer arrays showed improved tolerance against competing targets in an extracellular environment and potent bioavailability and targeting specificity in a xenograft tumor model in mice. This work may shed light on rationally designing multivalent ligand complexes of defined parameters with optimized binding avidity and targeting capability toward various applications in the biomedical fields.

Keywords:  DNA nanotechnology; EpCAM; aptamer arrays; enhanced binding avidity

DOI:  https://doi.org/10.1021/acs.nanolett.2c03377
Adv Mater. 2022 Dec 09. e2210267

Tetrahedral DNA Nanostructure with Interferon Stimulatory DNA Delivers Highly Potent Toxins Activates the cGAS-STING Pathway for Robust Chemotherapy and Immunotherapy.

Lingpu Zhang, Yuqi Wang, Johannes Karges, Dongsheng Tang, Hanchen Zhang, Kexuan Zou, Jie Song, Haihua Xiao.

  Tumor metastases and reoccurrences are considered the leading cause of cancer-associated deaths. While highly efficient treatments for the eradication of the primary tumor have been developed, the treatment of secondary or metastatic tumors remains poorly accessible. Over the last years, compounds that intervene through the immunogenic cGAS-STING signaling pathway against tumor metastases have emerged with potential for clinical development. While interferon stimulatory DNAs have demonstrated to activate this immunogenic pathway, these compounds are associated with poor bioavailability, poor stability, and poor cancer selectivity, rendering their use for therapeutic applications. Herein, the encapsulation of a highly potent chemotherapeutic platinum(II) complex and the incorporation of interferon stimulatory DNA strands for activation of the cGAS-STING pathway into multimodal tetrahedral DNA nanostructures (84bp-TDNISD/56MESS ) for combined chemotherapy and immunotherapy is reported. It is found that 84bp-TDNISD/56MESS could work as not only a drug delivery carrier for highly potent toxins but also an immunostimulant agent that can activate the STING pathway for anti-tumor immune responses. The nanomaterial demonstrated to nearly fully eradicate a primary as well as secondary/metastatic breast cancer tumor inside an animal model. This article is protected by copyright. All rights reserved.

Keywords:  Chemotherapy; DNA nanostructure; Immunotherapy; Interferon Stimulatory DNA; cGAS-STING Pathway

DOI:  https://doi.org/10.1002/adma.202210267
Nat Commun. 2022 Dec 05. 13(1): 7158

Self-assembling nanofibrous bacteriophage microgels as sprayable antimicrobials targeting multidrug-resistant bacteria.

Lei Tian, Leon He, Kyle Jackson, Ahmed Saif, Shadman Khan, Zeqi Wan, Tohid F Didar, Zeinab Hosseinidoust.

Nanofilamentous bacteriophages (bacterial viruses) are biofunctional, self-propagating, and monodisperse natural building blocks for virus-built materials. Minifying phage-built materials to microscale offers the promise of expanding the range function for these biomaterials to sprays and colloidal bioassays/biosensors. Here, we crosslink half a million self-organized phages as the sole structural component to construct each soft microgel. Through an in-house developed, biologics-friendly, high-throughput template method, over 35,000 phage-built microgels are produced from every square centimetre of a peelable microporous film template, constituting a 13-billion phage community. The phage-exclusive microgels exhibit a self-organized, highly-aligned nanofibrous texture and tunable auto-fluorescence. Further preservation of antimicrobial activity was achieved by making hybrid protein-phage microgels. When loaded with potent virulent phages, these microgels effectively reduce heavy loads of multidrug-resistant Escherichia coli O157:H7 on food products, leading to up to 6 logs reduction in 9 hours and rendering food contaminant free.

DOI: https://doi.org/10.1038/s41467-022-34803-7
Adv Mater. 2022 Dec 09. e2208568

Venation-Mimicking, Ultra-Stretchable, Room Temperature-Attachable Metal Tapes for Integrated Electronic Skins.

Bin Feng, Tianming Sun, Wengan Wang, Yu Xiao, Jinpeng Huo, Zhongyang Deng, Gongbo Bian, Yuxi Wu, Guisheng Zou, Wenxian Wang, Tianling Ren, Lei Liu.

  Future electronic skin systems require stretchable conductors and low-temperature integrations of external components, which remains challenging for traditional metal films. Herein, a bioinspired design concept is reported to endow metal films with 200% stretchability as well as room-temperature integration capability with diverse components. It is revealed that by controllable defects implantation, distinctive venation-mimicking cracking modes can be induced in strained metal films, leading to profound stretchability regulation. An intriguing exponential-to-linear transition of the film electromechanical performance is observed, which is elucidated by a unified model covering the essence of all modes. Combined with room-temperature integration capability, an integrated electronic skin is constructed with metal films serving as stretchable electrodes, diverse sensors, and "tapes" to attach subcomponents, showing prospects in helping disabled people. This one-step, defects implantation strategy is applicable to common metals without special substrate treatments, which enables fascinating ultra-stretchable metal film conductors with low-temperature integration capability to spark more sophisticated flexible electronic systems. This article is protected by copyright. All rights reserved.

Keywords:  bioinspired; electronic skin; flexible electronics; sensors; stretchable conductors

DOI:  https://doi.org/10.1002/adma.202208568
Nat Biomed Eng. 2022 Dec 05.

A library of base editors for the precise ablation of all protein-coding genes in the mouse mitochondrial genome.

Pedro Silva-Pinheiro, Christian D Mutti, Lindsey Van Haute, Christopher A Powell, Pavel A Nash, Keira Turner, Michal Minczuk.

The development of curative treatments for mitochondrial diseases, which are often caused by mutations in mitochondrial DNA (mtDNA) that impair energy metabolism and other aspects of cellular homoeostasis, is hindered by an incomplete understanding of the underlying biology and a scarcity of cellular and animal models. Here we report the design and application of a library of double-stranded-DNA deaminase-derived cytosine base editors optimized for the precise ablation of every mtDNA protein-coding gene in the mouse mitochondrial genome. We used the library, which we named MitoKO, to produce near-homoplasmic knockout cells in vitro and to generate a mouse knockout with high heteroplasmy levels and no off-target edits. MitoKO should facilitate systematic and comprehensive investigations of mtDNA-related pathways and their impact on organismal homoeostasis, and aid the generation of clinically meaningful in vivo models of mtDNA dysfunction.

DOI: https://doi.org/10.1038/s41551-022-00968-1
Nat Commun. 2022 Dec 09. 13(1): 7595

Closed-loop chemical recycling of cross-linked polymeric materials based on reversible amidation chemistry.

Bo Qin, Siyuan Liu, Zehuan Huang, Lingda Zeng, Jiang-Fei Xu, Xi Zhang.

Closed-loop chemical recycling provides a solution to the end-of-use problem of synthetic polymers. However, it remains a major challenge to design dynamic bonds, capable of effective bonding and reversible cleaving, for preparing chemically recyclable cross-linked polymers. Herein, we report a dynamic maleic acid tertiary amide bond based upon reversible amidation reaction between maleic anhydrides and secondary amines. This dynamic bond allows for the construction of polymer networks with tailorable and robust mechanical properties, covering strong elastomers with a tensile strength of 22.3 MPa and rigid plastics with a yield strength of 38.3 MPa. Impressively, these robust polymeric materials can be completely depolymerized in an acidic aqueous solution at ambient temperature, leading to efficient monomer recovery with >94% separation yields. Meanwhile, the recovered monomers can be used to remanufacture cross-linked polymeric materials without losing their original mechanical performance. This work unveils a general approach to design polymer networks with tunable mechanical performance and closed-loop recyclability, which will open a new avenue for sustainable polymeric materials.

DOI: https://doi.org/10.1038/s41467-022-35365-4
Adv Mater. 2022 Dec 07. e2206636

Fast and Dynamic Mapping of the Protein Corona on Nanoparticle Surfaces by Photocatalytic Proximity Labeling.

Zibin Zhang, Junji Ren, Wenbing Dai, Hua Zhang, Xueqing Wang, Bing He, Qiang Zhang.

  Protein corona broadly affects the delivery of nanomedicines in vivo. Although it has been widely studied by multiple strategies like centrifugal sedimentation, the rapidly forming mechanism and the dynamic structure of the protein corona at the seconds level remains challenging. Here, a photocatalytic proximity labeling technology in nanoparticles (nano-PPL) is developed. By fabricating a "core-shell" nanoparticle co-loaded with chlorin e6 catalyst and biotin-phenol probe, nano-PPL technology is validated for the rapid and precise labeling of corona proteins in situ. Nano-PPL significantly improves the temporal resolution of nano-protein interactions to 5 s duration compared with the classical centrifugation method (>30 s duration). Furthermore, nano-PPL achieves the fast and dynamic mapping of the protein corona on anionic and cationic nanoparticles, respectively. Finally, nano-PPL is deployed to verify the effect of the rapidly formed protein corona on the initial interaction of nanoparticles with cells. These findings highlight a significant methodological advance toward nano-protein interactions in the delivery of nanomedicines in vivo. This article is protected by copyright. All rights reserved.

Keywords:  Nanomedicines; biotinylation; nano-protein interaction; photocatalytic proximity labeling; protein corona

DOI:  https://doi.org/10.1002/adma.202206636
Nat Commun. 2022 Dec 03. 13(1): 7466

Engineered Lactococcus lactis secreting Flt3L and OX40 ligand for in situ vaccination-based cancer immunotherapy.

Junmeng Zhu, Yaohua Ke, Qin Liu, Ju Yang, Fangcen Liu, Ruihan Xu, Hang Zhou, Aoxing Chen, Jie Xiao, Fanyan Meng, Lixia Yu, Rutian Li, Jia Wei, Baorui Liu.

In situ vaccination is a promising strategy to convert the immunosuppressive tumor microenvironment into an immunostimulatory one with limited systemic exposure and side effect. However, sustained clinical benefits require long-term and multidimensional immune activation including innate and adaptive immunity. Here, we develop a probiotic food-grade Lactococcus lactis-based in situ vaccination (FOLactis) expressing a fusion protein of Fms-like tyrosine kinase 3 ligand and co-stimulator OX40 ligand. Intratumoural delivery of FOLactis contributes to local retention and sustained release of therapeutics to thoroughly modulate key components of the antitumour immune response, such as activation of natural killer cells, cytotoxic T lymphocytes, and conventional-type-1-dendritic cells in the tumors and tumor-draining lymph nodes. In addition, intratumoural administration of FOLactis induces a more robust tumor antigen-specific immune response and superior systemic antitumour efficacy in multiple poorly immune cell-infiltrated and anti-PD1-resistant tumors. Specific depletion of different immune cells reveals that CD8+ T and natural killer cells are crucial to the in situ vaccine-elicited tumor regression. Our results confirm that FOLactis displays an enhanced antitumour immunity and successfully converts the 'cold' tumors to 'hot' tumors.

DOI: https://doi.org/10.1038/s41467-022-35130-7
ACS Nano. 2022 Dec 05.

Efficient Tumor Eradication at Ultralow Drug Concentration via Externally Controlled and Boosted Metallic Iron Magnetoplasmonic Nanocapsules.

Arnon Fluksman, Aritz Lafuente, Zhi Li, Jordi Sort, Silvia Lope-Piedrafita, Maria José Esplandiu, Josep Nogues, Alejandro G Roca, Ofra Benny, Borja Sepulveda.

  With the aim to locally enhance the efficacy of cancer nanotherapies, here we present metal iron based magnetoplasmonic drug-loaded nanocapsules (MAPSULES), merging powerful external magnetic concentration in the tumor and efficient photothermal actuation to locally boost the drug therapeutic action at ultralow drug concentrations. The MAPSULES are composed of paclitaxel-loaded polylactic-co-glycolic acid (PLGA) nanoparticles partially coated by a nanodome shape iron/silica semishell. The iron semishell has been designed to present a ferromagnetic vortex for incorporating a large quantity of ferromagnetic material while maintaining high colloidal stability. The large iron semishell provides very strong magnetic manipulation via magnetophoretic forces, enabling over 10-fold higher trapping efficiency in microfluidic channels than typical superparamagnetic iron oxide nanoparticles. Moreover, the iron semishell exhibits highly damped plasmonic behavior, yielding intense broadband absorbance in the near-infrared biological windows and photothermal efficiency similar to the best plasmonic nanoheaters. The in vivo therapeutic assays in a mouse xenograft tumor model show a high amplification of the therapeutic effects by combining magnetic concentration and photothermal actuation in the tumor, leading to a complete eradication of the tumors at ultralow nanoparticle and drug concentration (equivalent to only 1 mg/kg PLGA nanoparticles containing 8 μg/kg of paclitaxel, i.e., 100-500-fold lower than the therapeutic window of the free and PLGA encapsulated drug and 13-3000-fold lower than current nanotherapies combining paclitaxel and light actuation). These results highlight the strength of this externally controlled and amplified therapeutic approach, which could be applied to locally boost a wide variety of drugs for different diseases.

Keywords:  breast cancer; magnetic manipulation; nanocapsules; paclitaxel; photothermal therapy

DOI:  https://doi.org/10.1021/acsnano.2c05733
Adv Mater. 2022 Dec 09. e2209556

Suppressing the dynamic oxygen evolution of sodium layered cathodes through synergistic surface dielectric polarization and bulk site-Selective Co-doping.

Xiao Xia, Tong Liu, Chen Cheng, Hongtai Li, Tianran Yan, Haolv Hu, Yihao Shen, Huanxin Ju, Ting-Shan Chan, Zhenwei Wu, Yuefeng Su, Yu Zhao, Duanyun Cao, Liang Zhang.

  Utilizing anionic redox activity within layered oxide cathode materials represents a transformational avenue for enabling high-energy-density rechargeable batteries. However, the anionic oxygen redox reaction is often accompanied with irreversible dynamic oxygen evolution, leading to unfavorable structural distortion and thus severe voltage decay and rapid capacity fading. Herein, we propose and validate that the dynamic oxygen evolution can be effectively suppressed through the synergistic surface CaTiO3 dielectric coating and bulk site-selective Ca/Ti co-doping for layered Na2/3 Ni1/3 Mn2/3 O2 . The surface dielectric coating layer not only suppresses the surface oxygen release but more importantly inhibits the bulk oxygen migration by creating a reverse electric field through dielectric polarization. Meanwhile, the site-selective doping of oxygen-affinity Ca into Na layers and Ti into transition metal layers effectively stabilizes the bulk oxygen through modulating the O 2p band center and the oxygen migration barrier. Such a strategy also leads to a reversible structural evolution with a low volume change because of the enhanced structural integrality and improved oxygen rigidity. Because of these synergistic advantages, the designed electrode exhibits greatly suppressed voltage decay and capacity fading upon long-term cycling. Our study affords a promising strategy for regulating the dynamic oxygen evolution to achieve high-capacity layered cathode materials. This article is protected by copyright. All rights reserved.

Keywords:  Layered oxide cathode; dielectric polarization; oxygen redox; oxygen release; site-selective co-doping; sodium-ion batteries

DOI:  https://doi.org/10.1002/adma.202209556
J Control Release. 2022 Dec 03. pii: S0168-3659(22)00808-2. [Epub ahead of print]

A nanosystem modulates immunosuppressive tumor microenvironment metabolism to amplify immunotherapy.

Huaiji Wang, Chenghao Wu, Xiaowen Tong, Shunjie Chen.

  In the immunosuppressive tumor microenvironment (iTME), lactate secretion by cancer cells facilitates cell escape via M1 to M2 macrophage polarization, and T cell exhaustion. Therefore, lactate is a promising tumor immunotherapy target. In this study, we constructed a biomimetic nanosystem to modulate iTME metabolism to amplify immunogenic cell death (ICD)-induced immunotherapy. Metal-organic frameworks were coated with platelet membranes (PM) for tumor site-specific delivery and rationally designed to carry lactate oxidase (Lox) which catalytically consumed lactate, while oxaliplatin (Oxa) induced ICD. Due to PM-mediated targeting, the biomimetic nanosystem selectively accumulated in tumors and inhibited tumor growth. Encouragingly, due to effective iTME modulation, enhanced cytotoxic T cell infiltration in tumors was observed. Also, tumor-associated macrophage (TAM) phenotypes were polarized from M2 to M1 types, and regulatory T cell (Treg) levels decreased in vivo. Increased CD8+ T to CD4+ T cell ratios in peripheral blood and spleen were also observed. Thus, our biomimetic nanosystem effectively modulated the iTME and inhibited tumor growth by consuming lactate and amplifying ICD-induced immunotherapy. We provide new avenues into cancer immunotherapy, with a specific emphasis on iTME modulation, which lays the foundation for translational biomimetic nanosystems in clinical settings.

Keywords:  Biomimetic nanosystem; Immunosuppressive tumor microenvironment; Lactate; Lactate oxidase; Oxaliplatin

DOI:  https://doi.org/10.1016/j.jconrel.2022.11.054
J Control Release. 2022 Dec 06. pii: S0168-3659(22)00825-2. [Epub ahead of print]

Evaluation in pig of an intestinal administration device for oral peptide delivery.

Staffan Berg, Teresia Uggla, Malin Antonsson, Sandro Filipe Nunes, Maria Englund, Louise Rosengren, Masoud Fahraj, Xiaoqiu Wu, Rydvikha Govender, Magnus Söderberg, David Janzén, Natalie Van Zuydam, Andreas Hugerth, Anette Larsson, Susanna Abrahmsén-Alami, Bertil Abrahamsson, Nigel Davies, Christel A S Bergström.

  The bioavailability of peptides co-delivered with permeation enhancers following oral administration remains low and highly variable. Two factors that may contribute to this are the dilution of the permeation enhancer in the intestinal fluid, as well as spreading of the released permeation enhancer and peptide in the lumen by intestinal motility. In this work we evaluated an Intestinal Administration Device (IAD) designed to reduce the luminal dilution of drug and permeation enhancer, and to minimize movement of the dosage form in the intestinal lumen. To achieve this, the IAD utilizes an expanding design that holds immediate release mini tablets and places these in contact with the intestinal epithelium, where unidirectional drug release can occur. The expanding conformation limits movement of the IAD in the intestinal tract, thereby enabling drug release at a single focal point in the intestine. A pig model was selected to study the ability of the IAD to promote intestinal absorption of the peptide MEDI7219 formulated together with the permeation enhancer sodium caprate. We compared the IAD to intestinally administered enteric coated capsules and an intestinally administered solution. The IAD restricted movement of the immediate release tablets in the small intestine and histological evaluation of the mucosa indicated that high concentrations of sodium caprate were achieved. Despite significant effect of the permeation enhancer on the integrity of the intestinal epithelium, the bioavailability of MEDI7219 was of the same order of magnitude as that achieved with the solution and enteric coated capsule formulations (2.5-3.8%). The variability in plasma concentrations of MEDI7219 were however lower when delivered using the IAD as compared to the solution and enteric coated capsule formulations. This suggests that dosage forms that can limit intestinal dilution and control the position of drug release can be a way to reduce the absorptive variability of peptides delivered with permeation enhancers but do not offer significant benefits in terms of increasing bioavailability.

Keywords:  Intestinal administration; MEDI7219; Oral peptide delivery; Permeation enhancer; Sodium caprate

DOI:  https://doi.org/10.1016/j.jconrel.2022.12.011
J Control Release. 2022 Nov 30. pii: S0168-3659(22)00798-2. [Epub ahead of print]

Enhanced immune responses to vaccine antigens in the corneal stroma.

Dengning Xia, Randall Toy, Pallab Pradhan, Amir Hejri, Jeremy Chae, Hans E Grossniklaus, Claus Cursiefen, Krishnendu Roy, Mark R Prausnitz.

  To examine the widely accepted dogma that the eye is an immune-privileged organ that can suppress antigen immunogenicity, we explored systemic immune responses to a model vaccine antigen (tetanus toxoid) delivered to six compartments of the rodent eye (ocular surface, corneal stroma, anterior chamber, subconjunctival space, suprachoroidal space, vitreous body). We discovered that antigens delivered to corneal stroma induced enhanced, rather than suppressed, antigen-specific immune responses, which were 18- to 30-fold greater than conventional intramuscular injection and comparable to intramuscular vaccination with alum adjuvant. Systemic immune responses to antigen delivered to the other ocular compartments were much weaker. The enhanced systemic immune responses after intrastromal injection were related to a sequence of events involving the formation of an antigen "depot" in the avascular stroma, infiltration of antigen-presenting cells, up-regulation of MHC class II and costimulatory molecules CD80/CD86, and induction of lymphangiogenesis in the corneal stroma facilitating sustained presentation of antigen to the lymphatic system. These enhanced immune responses in corneal stroma suggest new approaches to medical interventions for ocular immune diseases and vaccination methods.

Keywords:  Corneal stroma; Humoral vaccination response; Immune responses; Lymphangiogenesis; Ocular immune privilege; Vaccine kinetics

DOI:  https://doi.org/10.1016/j.jconrel.2022.11.045