bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022–01–16
twenty-two papers selected by
Ceren Kimna, Technical University of Munich
  1. Bioinspired Membrane-Disruptive Macromolecules as Drug-Free Therapeutics.
  2. miR-204-containing exosomes ameliorate GVHD-associated dry eye disease.
  3. An Aptamer-Modified DNA Tetrahedron-Based Nanogel for Combined Chemo/Gene Therapy of Multidrug-Resistant Tumors.
  4. Cation-Responsive and Photocleavable Hydrogels from Noncanonical Amphiphilic DNA Nanostructures.
  5. Promoting Nanoparticle Delivery Efficiency to Tumors by Locally Increasing Blood Flow There.
  6. Mitochondria-targeted polymer-celastrol conjugate with enhanced anticancer efficacy.
  7. A Facile, Protein-derived Supramolecular Theranostic Strategy for Multimodal-imaging-guided Photodynamic and Photothermal Immunotherapy in vivo.
  8. An automated all-in-one system for carbohydrate tracking, glucose monitoring, and insulin delivery.
  9. Maximizing response to intratumoral immunotherapy in mice by tuning local retention.
  10. Three Dimensional Microvascularized Tissue Models by Laser-Based Cavitation Molding of Collagen.
  11. Orchestrated Yolk-Shell Nanohybrids Regulate Macrophage Polarization and Dendritic Cell Maturation for Oncotherapy with Augmented Antitumor Immunity.
  12. Engineered Bacteria for Enhanced Radiotherapy against Breast Carcinoma.
  13. Self-Adaptive Single-Atom Catalyst Boosting Selective Ferroptosis in Tumor Cells.
  14. Mechano-Responsive Piezoelectric Nanofiber as an On-Demand Drug Delivery Vehicle.
  15. Self-Delivery Ternary Bioregulators for Photodynamic Amplified Immunotherapy by Tumor Microenvironment Reprogramming.
  16. Targeted editing and evolution of engineered ribosomes in vivo by filtered editing.
  17. Bionic Dormant Body of Timed Wake-Up for Bacteriotherapy in Vivo.
  18. Multifunctionalized Protein-Based Drug Delivery System for Inhibition of Tumor Growth and Progression.
  19. Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract.
  20. Yeast-derived nanoparticles remodel the immunosuppressive microenvironment in tumor and tumor-draining lymph nodes to suppress tumor growth.
  21. Stimulation of Probiotic Bacteria Induces Release of Membrane Vesicles with Augmented Anti-inflammatory Activity.
  22. Surface glycan targeting for cancer nano-immunotherapy.
  1. ACS Appl Bio Mater. 2020 Feb 17. 3(2): 1267-1275
    Bioinspired Membrane-Disruptive Macromolecules as Drug-Free Therapeutics.
    Feng Fan, Ji-Gang Piao, Yangyang Zhao, Lijun Jin, Mingyang Li, Yucai Wang, Lihua Yang.
      Membrane-disruptive, drug-free macromolecular therapeutics may help overcome cancer drug-resistance. Their inability to distinguish cancerous from normal cells, however, results in significant off-target toxicity. Note that the tumor has a slightly acidic microenvironment (pH 6.5-6.8) in contrast to the alkaline microenvironment in normal tissues (pH 7.4) and that host-defense peptides (HDPs) and their synthetic mimetics need to be net cationic to be membrane-disruptive. We herein endow polymer mimetics of HDPs with acid-triggered cationicity, to make them membrane-disruptive at only tumor pH. For these polymer mimetics, there exists a maximal threshold of chain length that determines whether the micelle of a mimetic inherits its pH-sensitive activity. Using the most and least active micelles as representatives, we find that their distinct potency in disrupting membranes arises because of their striking tendency to dissociate upon exposure to tumor pH. As expected, these micelles exhibit in vitro cytotoxicity profiles that correlate with their membrane-disruptive activity profiles. When administered intravenously, these micelles-irrespective of their distinct activity profiles-unanimously exhibit long systemic circulation as do PEGylated micelle nanoparticles, despite of their lacking stealth materials, owing to the zwitterionic nature of their surfaces at blood pH. Nevertheless, the pH-sensitive micelle achieves significantly higher tumor uptake and strikingly better therapeutic efficacy than its completely inactive analogue. More important, the pH-sensitive micelle exhibits undetectable off-target toxicity, owing to its pH-sensitivity. Clearly, making HDPs and their mimetics sensitive to tumor-characteristic cues (e.g., acidic pH) is efficient in minimizing their off-target toxicity, thereby offering membrane-disruptive, drug-free macromolecular therapeutics for fighting against cancer drug-resistance.
    Keywords:  bioinspired; drug-free; macromolecule; membrane-disruptive; pH-sensitive; tumor
    DOI:  https://doi.org/10.1021/acsabm.9b01143
  2. Sci Adv. 2022 Jan 14. 8(2): eabj9617
    miR-204-containing exosomes ameliorate GVHD-associated dry eye disease.
    Tian Zhou, Chang He, Peilong Lai, Ziqi Yang, Yan Liu, Huiyi Xu, Xiaojing Lin, Biyan Ni, Rong Ju, Wei Yi, Lingyi Liang, Duanqing Pei, Charles E Egwuagu, Xialin Liu.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/sciadv.abj9617
  3. ACS Appl Bio Mater. 2021 Oct 18. 4(10): 7701-7707
    An Aptamer-Modified DNA Tetrahedron-Based Nanogel for Combined Chemo/Gene Therapy of Multidrug-Resistant Tumors.
    Wantao Tang, Lin Han, Su Duan, Xuehe Lu, Yuang Wang, Xiaohui Wu, Jianbing Liu, Baoquan Ding.
      DNA-based nanogels have attracted much attention in the biomedical research field. Herein, we report a universal strategy for the fabrication of an aptamer-modified DNA tetrahedron (TET)-based nanogel for combined chemo/gene therapy of multidrug-resistant tumors. In our design, terminal extended antisense oligonucleotides (ASOs) are employed as the linker to co-assemble with two kinds of three-vertex extended TETs for the efficient construction of the DNA-based nanogel. With the incorporation of an active cell-targeting group (aptamer in one vertex of TET) and a controlled-release element (disulfide bridges in the terminals of ASOs), the functional DNA-based nanogel can achieve targeted cellular internalization and stimuli-responsive release of embedded ASOs. After loading with the chemodrug (doxorubicin (DOX), an intercalator of double-stranded DNA), the multifunctional DOX/Nanogel elicits efficient chemo/gene therapy of human MCF-7 breast tumor cells with DOX resistance (MCF-7R). This aptamer-modified DNA tetrahedron-based nanogel provides another strategy for intelligent drug delivery and combined tumor therapy.
    Keywords:  drug delivery; gene therapy; nucleic acid nanostructure; self-assembly; tumor therapy
    DOI:  https://doi.org/10.1021/acsabm.1c00933
  4. Nano Lett. 2022 Jan 13.
    Cation-Responsive and Photocleavable Hydrogels from Noncanonical Amphiphilic DNA Nanostructures.
    Giacomo Fabrini, Aisling Minard, Ryan A Brady, Marco Di Antonio, Lorenzo Di Michele.
      Thanks to its biocompatibility, versatility, and programmable interactions, DNA has been proposed as a building block for functional, stimuli-responsive frameworks with applications in biosensing, tissue engineering, and drug delivery. Of particular importance for in vivo applications is the possibility of making such nanomaterials responsive to physiological stimuli. Here, we demonstrate how combining noncanonical DNA G-quadruplex (G4) structures with amphiphilic DNA constructs yields nanostructures, which we termed "Quad-Stars", capable of assembling into responsive hydrogel particles via a straightforward, enzyme-free, one-pot reaction. The embedded G4 structures allow one to trigger and control the assembly/disassembly in a reversible fashion by adding or removing K+ ions. Furthermore, the hydrogel aggregates can be photo-disassembled upon near-UV irradiation in the presence of a porphyrin photosensitizer. The combined reversibility of assembly, responsiveness, and cargo-loading capabilities of the hydrophobic moieties make Quad-Stars a promising candidate for biosensors and responsive drug delivery carriers.
    Keywords:  Amphiphilic DNA; DNA nanotechnology; G-quadruplexes; self-assembly; stimuli-responsive hydrogels
    DOI:  https://doi.org/10.1021/acs.nanolett.1c03314
  5. ACS Appl Bio Mater. 2021 Oct 18. 4(10): 7615-7625
    Promoting Nanoparticle Delivery Efficiency to Tumors by Locally Increasing Blood Flow There.
    Feng Fan, Bin Xie, Lihua Yang.
      Enhancing the tumor-targeted delivery efficiency of nanoparticles is necessary for improving their therapeutic efficacy, yet how to fulfill this, especially in a practical manner, remains a significant challenge. Noticing that major organs compete effectively with tumors for nanoparticles, we herein carried out meta-analysis on nanoparticle delivery efficiency to major organs and tumors. Notably, in major organs, cellular uptake alone cannot explain why one organ has higher nanoparticle delivery efficiency than another; indeed, blood flow through an organ may facilitate nanoparticle delivery efficiency there as well. Intriguingly, such a facilitative role can be extrapolated to tumors, according to meta-analysis on the relationship of tumor-targeted delivery efficiency of nanoparticles versus blood flow through tumors of different weights. Indeed, using local mild hyperthermia as a model for modalities capable of increasing tumor blood flow, we observed a ∼3-fold increase in tumor-targeted delivery efficiency in the meta-analysis on studies involving both nanoparticles and local mild hyperthermia. This work identifies tumor blood flow as a crucial factor in determining tumor-targeted delivery efficiency of nanoparticles and suggests increasing tumor blood flow as an alternative way to boost tumor-targeted delivery efficiency of nanoparticles.
    Keywords:  delivery efficiency; local mild hyperthermia; nanomedicine; tumor; tumor blood flow
    DOI:  https://doi.org/10.1021/acsabm.1c00871
  6. J Control Release. 2022 Jan 05. pii: S0168-3659(22)00002-5. [Epub ahead of print]342 122-133
    Mitochondria-targeted polymer-celastrol conjugate with enhanced anticancer efficacy.
    Yu Geng, Jiajia Xiang, Shiqun Shao, Jianbin Tang, Youqing Shen.
      Celastrol, a natural triterpene extracted from traditional Chinese medicine, shows anticancer effects on various cancer cells. However, its poor water-solubility, short plasma half-life, and high systemic toxicity impede its applications in vivo, necessitating a stable drug delivery system to overcome these critical drawbacks. We present here a block copolymer, poly(2-(N-oxide-N,N-dimethylamino)ethyl methacrylate)-block-poly(2-hydroxyethyl methacrylate) (OPDMA-HEMA), as the carrier for celastrol delivery. The amphiphilic polymer-celastrol conjugate can self-assemble into nanoparticles in aqueous solutions. The OPDMA outer shell confers the nanoparticles with improved pharmacokinetics and efficient mitochondria targeting capacity, and profoundly potentiates celastrol's induction of immunogenic cell death, which collectively contribute to the enhanced therapeutic effects of celastrol in vivo. This mitochondria-targeted polymer-celastrol conjugate may promise the applications of celastrol in cancer treatment.
    Keywords:  Cancer therapy; Celastrol; Mitochondria; N-oxide; Polymer-drug conjugate
    DOI:  https://doi.org/10.1016/j.jconrel.2022.01.002
  7. Adv Mater. 2022 Jan 11. e2109111
    A Facile, Protein-derived Supramolecular Theranostic Strategy for Multimodal-imaging-guided Photodynamic and Photothermal Immunotherapy in vivo.
    Hong-Bo Cheng, Hao Dai, Xiaoqiong Tan, Hao Li, Huihui Liang, Chenyan Hu, Mingwei Huang, Jin Yong Lee, Jing Zhao, Liming Zhou, Yuguang Wang, Liqun Zhang, Juyoung Yoon.
      Theranostic systems that permit both diagnosis and treatment in vivo are highly appealing means by which to meet the demands of precision medicine. However, most such systems remain subject to issues related to complex molecular design and synthesis, potential toxicity, and possible photoactivity changes. Herein, we propose a novel supramolecular theranostic strategy involving biomarker protein activation (BPA) and a host-guest strategy. To exemplify BPA, we demonstrate a facile "one-for-all" nanotheranostic agent for both albumin detection and cancer treatment that utilizes a nanoparticulate heavy-atom-free BODIPY dye derivative (B4 NPs). The fluorescence and photoactivity of BODIPY dyes are completely suppressed by aggregation-induced self-quenching in the nanoparticulate state. However, a Balb/c nude mouse model was used to confirm that, following the disassembly of injected B4 NPs, BODIPY specifically binds albumin in vivo, accompanied by significantly enhanced biocompatibility and photothermal conversion efficiency (PCE). More importantly, our supramolecular host-guest BPA strategy enables the resultant nanoplatform to act as a facile and efficient strategy for photodynamic and photothermal immunotherapy. This article is protected by copyright. All rights reserved.
    Keywords:  cancer therapy; enhanced photothermal efficiency; heavy-atom-free BODIPY; host-guest strategy
    DOI:  https://doi.org/10.1002/adma.202109111
  8. J Control Release. 2022 Jan 05. pii: S0168-3659(22)00001-3. [Epub ahead of print]
    An automated all-in-one system for carbohydrate tracking, glucose monitoring, and insulin delivery.
    Hen-Wei Huang, Siheng Sean You, Luca Di Tizio, Canchen Li, Erin Raftery, Claas Ehmke, Christoph Steiger, Junwei Li, Adam Wentworth, Ian Ballinger, Declan Gwynne, Kewang Nan, Jia Y Liang, Jason Li, James D Byrne, Joy Collins, Siddartha Tamang, Keiko Ishida, Florencia Halperin, Giovanni Traverso.
      Glycemic control through titration of insulin dosing remains the mainstay of diabetes mellitus treatment. Insulin therapy is generally divided into dosing with long- and short-acting insulin, where long-acting insulin provides basal coverage and short-acting insulin supports glycemic excursions associated with eating. The dosing of short-acting insulin often involves several steps for the user including blood glucose measurement and integration of potential carbohydrate loads to inform safe and appropriate dosing. The significant burden placed on the user for blood glucose measurement and effective carbohydrate counting can manifest in substantial effects on adherence. Through the application of computer vision, we have developed a smartphone-based system that is able to detect the carbohydrate load of food by simply taking a single image of the food and converting that information into a required insulin dose by incorporating a blood glucose measurement. Moreover, we report the development of comprehensive all-in-one insulin delivery systems that streamline all operations that peripheral devices require for safe insulin administration, which in turn significantly reduces the complexity and time required for titration of insulin. The development of an autonomous system that supports maximum ease and accuracy of insulin dosing will transform our ability to more effectively support patients with diabetes.
    DOI:  https://doi.org/10.1016/j.jconrel.2022.01.001
  9. Nat Commun. 2022 Jan 10. 13(1): 109
    Maximizing response to intratumoral immunotherapy in mice by tuning local retention.
    Noor Momin, Joseph R Palmeri, Emi A Lutz, Noor Jailkhani, Howard Mak, Anthony Tabet, Magnolia M Chinn, Byong H Kang, Virginia Spanoudaki, Richard O Hynes, K Dane Wittrup.
      Direct injection of therapies into tumors has emerged as an administration route capable of achieving high local drug exposure and strong anti-tumor response. A diverse array of immune agonists ranging in size and target are under development as local immunotherapies. However, due to the relatively recent adoption of intratumoral administration, the pharmacokinetics of locally-injected biologics remains poorly defined, limiting rational design of tumor-localized immunotherapies. Here we define a pharmacokinetic framework for biologics injected intratumorally that can predict tumor exposure and effectiveness. We find empirically and computationally that extending the tumor exposure of locally-injected interleukin-2 by increasing molecular size and/or improving matrix-targeting affinity improves therapeutic efficacy in mice. By tracking the distribution of intratumorally-injected proteins using positron emission tomography, we observe size-dependent enhancement in tumor exposure occurs by slowing the rate of diffusive escape from the tumor and by increasing partitioning to an apparent viscous region of the tumor. In elucidating how molecular weight and matrix binding interplay to determine tumor exposure, our model can aid in the design of intratumoral therapies to exert maximal therapeutic effect.
    DOI:  https://doi.org/10.1038/s41467-021-27390-6
  10. Adv Mater. 2022 Jan 14. e2109823
    Three Dimensional Microvascularized Tissue Models by Laser-Based Cavitation Molding of Collagen.
    Alessandro Enrico, Dimitrios Voulgaris, Rebecca Östmans, Naveen Sundaravadivel, Lucille Moutaux, Aurélie Cordier, Frank Niklaus, Anna Herland, Göran Stemme.
      3D tissue models recapitulating human physiology are important for fundamental biomedical research, and they hold promise to become a new tool in drug development. An integrated and defined microvasculature in 3D tissue models is necessary for optimal cell functions. However, conventional bioprinting only allows the fabrication of hydrogel scaffolds containing vessel-like structures with large diameters (>100 μm) and simple geometries. Recent developments in laser photoablation enable the generation of this type of structure with higher resolution and complexity, but the photo-thermal process can compromise cell viability and hydrogel integrity. To address these limitations, the present work reports in-situ 3D patterning of collagen hydrogels by femtosecond laser irradiation to create channels and cavities with diameters ranging from 20 to 60 μm. In this process, laser irradiation of the hydrogel generates cavitation gas bubbles that rearrange the collagen fibers, thereby creating stable microchannels. Such 3D channels can be formed in cell- and organoid-laden hydrogel without affecting the viability outside the lumen and can enable the formation of artificial microvasculature by the culture of endothelial cells and cell media perfusion. Thus, this method enables organs-on-a-chip and 3D tissue models featuring complex microvasculature. This article is protected by copyright. All rights reserved.
    Keywords:  3D micromachining; direct writing; femtosecond laser; microvasculature; tissue engineering; type I collagen
    DOI:  https://doi.org/10.1002/adma.202109823
  11. Adv Mater. 2022 Jan 11. e2108263
    Orchestrated Yolk-Shell Nanohybrids Regulate Macrophage Polarization and Dendritic Cell Maturation for Oncotherapy with Augmented Antitumor Immunity.
    Xiaoyi Zhao, Kangli Guo, Kai Zhang, Shun Duan, Meiwan Chen, Nana Zhao, Fu-Jian Xu.
      The protumoral and immunosuppressive tumor microenvironments (TME) greatly limit the antitumor immune responses of nanoparticles for cancer immunotherapy. Here, we explore the intrinsic immunomodulatory effects of orchestrated nanoparticles and their ability to simultaneously trigger tumor antigen release, thereby reversing immunosuppression and achieving potent antitumor immunity and augmented cancer therapy. By optimizing both the composition and morphology, a facile strategy is proposed to construct yolk-shell nanohybrids (Fe3 O4 @C/MnO2 -PGEA, FCMP). The intrinsic immunomodulatory effects of FCMP are utilized to reprogram macrophages to M1 phenotype and induce the maturation of dendritic cells, which regulate the immunosuppressive TME. In addition, the chemical, magnetic, and optical properties of FCMP contribute to amplified immunogenic cell death induced by multi-augmented chemodynamic therapy (CDT) and synergistic tumor treatment. Taking advantage of the unique yolk-shell structure, accurate T1 -T2 dual-mode magnetic resonance imaging can be realized and CDT can be maximized through sufficient exposure of both the Fe3 O4 core and MnO2 shell. Potent antitumor effects are found to substantially inhibit the growth of both primary and distant tumors. Furthermore, the strategy could be extended to the synthesis of other yolk-shell nanohybrids with tailored properties since the cores are tunable. This work establishes a novel strategy for the fabrication of multifunctional nanoplatforms with yolk-shell structure for effective cancer therapy with immunomodulation-enhanced antitumor immunity. This article is protected by copyright. All rights reserved.
    Keywords:  antitumor immunity; chemodynamic therapy; immunomodulatory effect; tumor microenvironment; yolk-shell structure
    DOI:  https://doi.org/10.1002/adma.202108263
  12. ACS Nano. 2022 Jan 14.
    Engineered Bacteria for Enhanced Radiotherapy against Breast Carcinoma.
    Pei Pan, Xue Dong, Ying Chen, Xuan Zeng, Xian-Zheng Zhang.
      Radiotherapy is widely applied for multiple malignant tumors ablation in the clinic. However, redundant doses of X-rays might destroy normal tissue in the periphery of tumor sites. Here, we developed an integrated nanosystem (Bac@BNP) composed of engineered bacteria (Bac) and Bi2S3 nanoparticles (BNPs) for sensitizing radiotherapy. Bac could target and colonize in tumor sites alternatively, which overexpressed cytolysin A (ClyA) protein to regulate the cell cycle from a radioresistant phase to a radiosensitive phase. Simultaneously, peptide-modified BNPs, as a radiosensitizer with a high-Z element, was released from the surface of Bac owing to the matrix metalloproteinase-2 (MMP-2) response in the tumor microenvironment. Under X-ray irradiation, BNPs could enhance the radiotherapy sensitivity by triggering the intracellular generation of reactive oxygen species (ROS), coupled with DNA damage. In this constructed nanosystem, the combination of Bac@BNP and X-ray irradiation led to significant suppression of breast carcinoma in murine models with reduced side effects.
    Keywords:  bacterial; cell cycle; nanoparticle; radiosentization; tumor therapy
    DOI:  https://doi.org/10.1021/acsnano.1c08350
  13. ACS Nano. 2022 Jan 13.
    Self-Adaptive Single-Atom Catalyst Boosting Selective Ferroptosis in Tumor Cells.
    Fangfang Cao, Yanjuan Sang, Chaoying Liu, Fuquan Bai, Lirong Zheng, Jinsong Ren, Xiaogang Qu.
      Ferroptosis, resulting from the catastrophic accumulation of lipid reactive oxygen species (ROS) and the inactivation of glutathione (GSH)-dependent peroxidase 4 (GPX4), has emerged as a form of regulated cell death for cancer therapy. Despite progress made with current ferroptosis inducers, efficient systems to trigger ferroptosis remain challenging, owing largely to their low activity, uncontrollable behavior, and even nonselective interactions. Here, we report a self-adaptive ferroptosis platform by engineering a DNA modulator onto the surface of single-atom nanozymes (SAzymes). The modulator could not only specifically intensify the ROS-generating activity but also endow the SAzymes with on-demand GSH-consuming ability in tumor cells, accelerating selective and safe ferroptosis. The self-adaptive antitumor response has been demonstrated in colon cancer and breast cancer, promoting the development of selective cancer therapy.
    Keywords:  DNA modulation; ROS regulation; activated GSH-consuming; selective ferroptosis; self-adaptive; single-atom catalysis
    DOI:  https://doi.org/10.1021/acsnano.1c08464
  14. ACS Appl Bio Mater. 2021 Apr 19. 4(4): 3706-3715
    Mechano-Responsive Piezoelectric Nanofiber as an On-Demand Drug Delivery Vehicle.
    Tanvi Jariwala, Gerardo Ico, Youyi Tai, Honghyun Park, Nosang V Myung, Jin Nam.
      The control over biodistribution and pharmacokinetics is critical to enhance the efficacy and minimize the side effects of therapeutic agents. To address the need for an on-demand drug delivery system for precise control over the release time and the quantity of drugs, we exploited the mechano-responsiveness of piezoelectric poly(vinylidene fluoride-trifluroethylene) (P(VDF-TrFE)) nanofibers for drug delivery applications. The large surface area-to-volume ratio inherent to nanomaterials, together with the transformative piezoelectric properties, allowed us to use the material as an ultrasensitive and mechano-responsive drug delivery platform driven by the direct piezoelectric effect. The intrinsic negative zeta potential of the nanofibers was utilized to electrostatically load cationic drug molecules, where surface potential changes by exogenous mechanical actuation trigger the release of drug molecules. We show that the drug release kinetics of the P(VDF-TrFE) nanofibers depends on the fiber diameter, thus piezoelectric properties. We further demonstrated that the drug release quantity can be tuned by the applied pressure or dose of physiologically safe corporeal shockwaves as a mechanical stimulus in in vitro and ex vivo models. Overall, we demonstrated the utility of piezoelectric electrospun nanofibers for mechano-responsive controlled drug release.
    Keywords:  electrospun fibers; mechano-sensitive; on-demand drug delivery; piezoelectric; poly(vinylidene trifluoroethylene)
    DOI:  https://doi.org/10.1021/acsabm.1c00232
  15. ACS Nano. 2022 Jan 13.
    Self-Delivery Ternary Bioregulators for Photodynamic Amplified Immunotherapy by Tumor Microenvironment Reprogramming.
    Lin-Ping Zhao, Rong-Rong Zheng, Ren-Jiang Kong, Chu-Yu Huang, Xiao-Na Rao, Ni Yang, A-Li Chen, Xi-Yong Yu, Hong Cheng, Shi-Ying Li.
      Abnormal metabolism of cancer cells results in complex tumor microenvironments (TME), which play a dominant role in tumor metastasis. Herein, self-delivery ternary bioregulators (designated as TerBio) are constructed for photodynamic amplified immunotherapy against colorectal cancer by TME reprogramming. Specifically, carrier-free TerBio are prepared by the self-assembly of chlorine e6, SB505124 (SB), and lonidamine (Lon), which exhibit improved tumor accumulation, tumor penetration, and cellular uptake behaviors. Interestingly, TerBio-mediated photodynamic therapy (PDT) could not only inhibit the primary tumor growth but also induce immunogenic cell death of tumors to activate the cascade immune response. Furthermore, TerBio are capable of TME reprograming by SB-triggered transforming growth factor (TGF)-β blockage and Lon-induced lactic acid efflux inhibition. As a consequence, TerBio significantly suppresses distant and metastatic tumor growth by PDT-amplified immunotherapy. This study might advance the development of self-delivery nanomedicine against malignant tumor growth and metastasis.
    Keywords:  immunotherapy; photodynamic therapy; reprogramming; self-delivery; tumor microenvironment
    DOI:  https://doi.org/10.1021/acsnano.1c08978
  16. Nat Commun. 2022 Jan 10. 13(1): 180
    Targeted editing and evolution of engineered ribosomes in vivo by filtered editing.
    Felix Radford, Shane D Elliott, Alanna Schepartz, Farren J Isaacs.
      Genome editing technologies introduce targeted chromosomal modifications in organisms yet are constrained by the inability to selectively modify repetitive genetic elements. Here we describe filtered editing, a genome editing method that embeds group 1 self-splicing introns into repetitive genetic elements to construct unique genetic addresses that can be selectively modified. We introduce intron-containing ribosomes into the E. coli genome and perform targeted modifications of these ribosomes using CRISPR/Cas9 and multiplex automated genome engineering. Self-splicing of introns post-transcription yields scarless RNA molecules, generating a complex library of targeted combinatorial variants. We use filtered editing to co-evolve the 16S rRNA to tune the ribosome's translational efficiency and the 23S rRNA to isolate antibiotic-resistant ribosome variants without interfering with native translation. This work sets the stage to engineer mutant ribosomes that polymerize abiological monomers with diverse chemistries and expands the scope of genome engineering for precise editing and evolution of repetitive DNA sequences.
    DOI:  https://doi.org/10.1038/s41467-021-27836-x
  17. ACS Nano. 2022 Jan 13.
    Bionic Dormant Body of Timed Wake-Up for Bacteriotherapy in Vivo.
    Mingming Guo, Chunrui Yang, Bowen Li, Shi-Xiang Cheng, Qinglu Guo, Dong Ming, Bin Zheng.
      The microorganism has become a promising therapeutic tool for many diseases because it is a kind of cell factory that can efficiently synthesize a variety of bioactive substances. However, the metabolic destiny of microorganisms is difficult to predict in vivo. Here, a timing bionic dormant body with programmable destiny is reported, which can predict the metabolic time and location of microorganisms in vivo and can prevent it from being damaged by the complex biological environment in vivo. Taking the complex digestive system as an example, the bionic dormant body exists in the upper digestive tract as a nonmetabolic dormant body after oral administration and will be awakened to synthesize bioactive substances about 2 h after reaching the intestine. Compared with oral microorganisms alone, the bioavailability of the biomimetic dormant body in the intestine is almost 3.5 times higher. The utilization rate of the oral bionic dormant body to synthesize drugs is 2.28 times higher than oral drugs. We demonstrated the significant efficacies of treatment using Parkinson's disease (PD) mice by dormant body capable of timed neurotransmitter production after oral delivery. The timed bionic dormant body with programmable destiny may provide an effective technology to generate advanced microbial therapies for the treatment of various diseases.
    Keywords:  Parkinson’s Disease (PD); bacteriotherapy; bionic dormant body; timed wake-up; γ-aminobutyric acid (GABA)
    DOI:  https://doi.org/10.1021/acsnano.1c08377
  18. ACS Appl Bio Mater. 2020 May 18. 3(5): 3196-3202
    Multifunctionalized Protein-Based Drug Delivery System for Inhibition of Tumor Growth and Progression.
    Yin Qin, Lei Xu, Ying-Ying Guan, Hong Liu.
      To improve the bioavailability of hydrophobic drugs and realize tumor targeting therapeutic actions efficiently, a nanosized multifunctional protein-based drug delivery system was constructed by self-assembly in a facile manner. Negatively charged cRGD-conjugated bovine serum albumin (cRGD-BSA) loaded with a hydrophobic antitumor drug (curcumin, CUR) was complexed with electropositive protamine sulfate (PS) via electroattractive forces to form CUR@cRGD-BSA/PS nanoparticles. Flow cytometry and confocal microscopy show that the multifunctional CUR@cRGD-BSA/PS nanoparticles lead to significantly increased intracellular drug accumulation in tumor cells owing to the tumor specific affinity of cRGD ligands as well as the membrane translocating property of PS. As a result, the multifunctional protein-based delivery system (CUR@cRGD-BSA/PS) exhibits an apparently enhanced inhibitory efficiency on malignant cells as compared with free CUR and the monofunctional delivery system (CUR@cRGD-BSA). More importantly, the expression of proteins (Bcl-2, cyclin D1, β-catenin, c-Myc, and MMP-9) involved in cancer development in the tumor cells treated by CUR@cRGD-BSA/PS is dramatically downregulated, implying the functional protein-based drug delivery system can effectively prevent tumor progression. Our investigation gives insight into the construction of multifunctional protein-based delivery carriers for tumor targeting delivery of hydrophobic drugs.
    Keywords:  anticancer; cRGD; curcumin; drug delivery; protein carriers; tumor targeting
    DOI:  https://doi.org/10.1021/acsabm.0c00190
  19. Nat Commun. 2022 Jan 10. 13(1): 136
    Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract.
    Jianan Zhang, Morgan E Walker, Katherine Z Sanidad, Hongna Zhang, Yanshan Liang, Ermin Zhao, Katherine Chacon-Vargas, Vladimir Yeliseyev, Julie Parsonnet, Thomas D Haggerty, Guangqiang Wang, Joshua B Simpson, Parth B Jariwala, Violet V Beaty, Jun Yang, Haixia Yang, Anand Panigrahy, Lisa M Minter, Daeyoung Kim, John G Gibbons, LinShu Liu, Zhengze Li, Hang Xiao, Valentina Borlandelli, Hermen S Overkleeft, Erica W Cloer, Michael B Major, Dennis Goldfarb, Zongwei Cai, Matthew R Redinbo, Guodong Zhang.
      Emerging research supports that triclosan (TCS), an antimicrobial agent found in thousands of consumer products, exacerbates colitis and colitis-associated colorectal tumorigenesis in animal models. While the intestinal toxicities of TCS require the presence of gut microbiota, the molecular mechanisms involved have not been defined. Here we show that intestinal commensal microbes mediate metabolic activation of TCS in the colon and drive its gut toxicology. Using a range of in vitro, ex vivo, and in vivo approaches, we identify specific microbial β-glucuronidase (GUS) enzymes involved and pinpoint molecular motifs required to metabolically activate TCS in the gut. Finally, we show that targeted inhibition of bacterial GUS enzymes abolishes the colitis-promoting effects of TCS, supporting an essential role of specific microbial proteins in TCS toxicity. Together, our results define a mechanism by which intestinal microbes contribute to the metabolic activation and gut toxicity of TCS, and highlight the importance of considering the contributions of the gut microbiota in evaluating the toxic potential of environmental chemicals.
    DOI:  https://doi.org/10.1038/s41467-021-27762-y
  20. Nat Commun. 2022 Jan 10. 13(1): 110
    Yeast-derived nanoparticles remodel the immunosuppressive microenvironment in tumor and tumor-draining lymph nodes to suppress tumor growth.
    Jialu Xu, Qingle Ma, Yue Zhang, Ziying Fei, Yifei Sun, Qin Fan, Bo Liu, Jinyu Bai, Yue Yu, Jianhong Chu, Jingrun Chen, Chao Wang.
      Microbe-based cancer immunotherapy has recently emerged as a hot topic for cancer treatment. However, serious limitations remain including infection associated side-effect and unsatisfactory outcomes in clinic trials. Here, we fabricate different sizes of nano-formulations derived from yeast cell wall (YCW NPs) by differential centrifugation. The induction of anticancer immunity of our formulations appears to inversely correlate with their size due to the ability to accumulate in tumor-draining lymph node (TDLN). Moreover, we use a percolation model to explain their distribution behavior toward TDLN. The abundance and functional orientation of each effector component are significantly improved not only in the microenvironment in tumor but also in the TDLN following small size YCW NPs treatment. In combination with programmed death-ligand 1 (PD-L1) blockade, we demonstrate anticancer efficiency in melanoma-challenged mice. We delineate potential strategy to target immunosuppressive microenvironment by microbe-based nanoparticles and highlight the role of size effect in microbe-based immune therapeutics.
    DOI:  https://doi.org/10.1038/s41467-021-27750-2
  21. ACS Appl Bio Mater. 2021 May 17. 4(5): 3739-3748
    Stimulation of Probiotic Bacteria Induces Release of Membrane Vesicles with Augmented Anti-inflammatory Activity.
    Lisann Müller, Thomas Kuhn, Marcus Koch, Gregor Fuhrmann.
      During infection, inflammation is an important contributor to tissue regeneration and healing, but it may also negatively affect these processes should chronic overstimulation take place. Similar issues arise in chronic inflammatory gastrointestinal diseases such as inflammatory bowel diseases or celiac disease, which show increasing incidences worldwide. For these dispositions, probiotic microorganisms, including lactobacilli, are studied as an adjuvant therapy to counterbalance gut dysbiosis. However, not all who are affected can benefit from the probiotic treatment, as immunosuppressed or hospitalized patients can suffer from bacteremia or sepsis when living microorganisms are administered. A promising alternative is the treatment with bacteria-derived membrane vesicles that confer similar beneficial effects as the progenitor strains themselves. Membrane vesicles from lactobacilli have shown anti-inflammatory therapeutic effects, but it remains unclear whether the stimulation of probiotics induces vesicles that are more efficient. Here, the influence of culture conditions on the anti-inflammatory characteristics of Lactobacillus membrane vesicles was investigated. We reveal that the culture conditions of two Lactobacillus strains, namely, L. casei and L. plantarum, can be optimized to increase the anti-inflammatory effect of their vesicles. Five different cultivation conditions were tested, including pH manipulation, agitation rate, and oxygen supply, and the produced membrane vesicles were characterized physico-chemically regarding size, yield, and zeta potential. We furthermore analyzed the anti-inflammatory effect of the purified vesicles in macrophage inflammation models. Compared to standard cultivation conditions, vesicles obtained from L. casei cultured at pH 6.5 and agitation induced the strongest interleukin-10 release and tumor necrosis factor-α reduction. For L. plantarum, medium adjusted to pH 5 had the most pronounced effect on the anti-inflammatory activity of their vesicles. Our results reveal that the anti-inflammatory effect of probiotic vesicles may be potentiated by expanding different cultivation conditions for lactobacilli. This study creates an important base for the utilization of probiotic membrane vesicles to treat inflammation.
    Keywords:  anti-inflammatory therapy; autoimmune dispositions; bacteriomimetics; biomimetics; extracellular vesicles
    DOI:  https://doi.org/10.1021/acsabm.0c01136
  22. J Control Release. 2022 Jan 05. pii: S0168-3659(22)00004-9. [Epub ahead of print]
    Surface glycan targeting for cancer nano-immunotherapy.
    Yonghyun Choi, Jiwon Kim, Jayoung Chae, Joohye Hong, Jongjun Park, Eunseo Jeong, Hayoung Kim, Masayoshi Tanaka, Mina Okochi, Jonghoon Choi.
      Cancer immunotherapy is an emerging therapeutic strategy for cancer treatment. Most of the immunotherapeutics approved by the FDA regulate the innate immune system and associated immune cell activity, with immune check inhibitors in particular having transformed the field of cancer immunotherapy due to their significant clinical potential. However, previously reported immunotherapeutics have exhibited undesirable side effects, including autoimmune toxicity and inflammation. Controlling these deleterious responses and designing therapeutics that can precisely target specific regions are thus crucial to improving the efficacy of cancer immunotherapies. Recent studies have reported that cancer cells employ glycan-immune checkpoint interactions to modulate immune cell activity. Thus, the recognition of cancer glycan moieties such as sialoglycans may improve the anticancer activity of immune cells. In this review, we discuss recent advances in cancer immunotherapies involving glycans and glycan-targeting technologies based on nanomaterial-assisted local delivery systems.
    Keywords:  Cancer glycan; Cancer immunotherapy; Glycan targeting; Glycosylation; Nanoparticle
    DOI:  https://doi.org/10.1016/j.jconrel.2022.01.004
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