bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022–11–27
fourteen papers selected by
Ceren Kimna, Technical University of Munich
  1. Substituting racemic ionizable lipids with stereopure ionizable lipids can increase mRNA delivery.
  2. Lectin-based phototherapy targeting cell surface glycans for pancreatic cancer.
  3. Multiplexed Organelles Portrait Barcodes for Subcellular MicroRNA Array Detection in Living Cells.
  4. Antitumor activity of anti-miR-21 delivered through lipid nanoparticles.
  5. Polymeric micelles effectively reprogram the tumor microenvironment to potentiate nano-immunotherapy in mouse breast cancer models.
  6. Compact zinc finger base editors that edit mitochondrial or nuclear DNA in vitro and in vivo.
  7. Optimization of storage conditions for lipid nanoparticle-formulated self-replicating RNA vaccines.
  8. Platelet Membrane Cloaked Nanotubes to Accelerate Thrombolysis by Thrombus Clot-Targeting and Penetration.
  9. Reversible covalent nanoassemblies for augmented nuclear drug translocation in drug resistance tumor.
  10. Biomimetic Microadhesion Guided Instant Spinning.
  11. Engineering bacteria as interactive cancer therapies.
  12. Size-switchable polymer-based nanomedicines in the advanced therapy of rheumatoid arthritis.
  13. Self-healing electronics for prognostic monitoring of methylated circulating tumor DNAs.
  14. Functionally integrating nanoparticles alleviate deep vein thrombosis in pregnancy and rescue intrauterine growth restriction.
  1. J Control Release. 2022 Nov 21. pii: S0168-3659(22)00782-9. [Epub ahead of print]
    Substituting racemic ionizable lipids with stereopure ionizable lipids can increase mRNA delivery.
    Alejandro J Da Silva Sanchez, Kun Zhao, Sebastian G Huayamares, Marine Z C Hatit, Melissa P Lokugamage, David Loughrey, Curtis Dobrowolski, Shuaishuai Wang, Hyejin Kim, Kalina Paunovska, Yanina Kuzminich, James E Dahlman.
      Lipid nanoparticles (LNPs) have delivered siRNA and mRNA drugs in humans, underscoring the potential impact of improving the therapeutic window of next-generation LNPs. To increase the LNP therapeutic window, we applied lessons from small-molecule chemistry to ionizable lipid design. Specifically, given that stereochemistry often influences small-molecule safety and pharmacokinetics, we hypothesized that the stereochemistry of lipids within an LNP would influence mRNA delivery. We tested this hypothesis in vivo using 128 novel LNPs that included stereopure derivatives of C12-200, an ionizable lipid that when formulated into LNPs delivers RNA in mice and non-human primates but is not used clinically due to its poor tolerability. We found that a novel C12-200-S LNP delivered up to 2.8-fold and 6.1-fold more mRNA in vivo than its racemic and C12-200-R controls, respectively. To identify the potential causes leading to increased delivery, we quantified LNP biophysical traits and concluded that these did not change with stereochemistry. Instead, we found that stereopure LNPs were better tolerated than racemic LNPs in vivo. These data suggest that LNP-mediated mRNA delivery can be improved by designing LNPs to include stereopure ionizable lipids.
    Keywords:  Lipid nanoparticles; Stereochemistry; mRNA
    DOI:  https://doi.org/10.1016/j.jconrel.2022.11.037
  2. Int J Cancer. 2022 Nov 22.
    Lectin-based phototherapy targeting cell surface glycans for pancreatic cancer.
    Yukihito Kuroda, Tatsuya Oda, Osamu Shimomura, Shinji Hashimoto, Yoshimasa Akashi, Yoshihiro Miyazaki, Kinji Furuya, Tomoaki Furuta, Hiromitsu Nakahashi, Pakavarin Louphrasitthiphol, Bryan J Mathis, Takahito Nakajima, Hiroaki Tateno.
      Pancreatic ductal adenocarcinoma (PDAC) is resistant to current treatments but lectin-based therapy targeting cell surface glycans could be a promising new horizon. Here, we report a novel lectin-based phototherapy (Lec-PT) that combines the PDAC targeting ability of rBC2LCN lectin to a photoabsorber, IRDye700DX (rBC2-IR700), resulting in a novel and highly specific near-infrared, light-activated, anti-PDAC therapy. Lec-PT cytotoxicity was first verified in vitro with a human PDAC cell line, Capan-1, indicating that rBC2-IR700 is only cytotoxic upon cellular binding and exposure to near-infrared light. The therapeutic efficacy of Lec-PT was subsequently verified in vivo using cell lines and patient-derived, subcutaneous xenografting into nude mice. Significant accumulation of rBC2-IR700 occurs as early as 2 hours post-intravenous administration while cytotoxicity is only achieved upon exposure to near-infrared light. Repeated treatments further slowed tumor growth. Lec-PT was also assessed for off-target toxicity in the orthotopic xenograft model. Shielding of intraperitoneal organs from near-infrared light minimized off-target toxicity. Using readily available components, Lec-PT specifically targeted pancreatic cancer with high reproducibility and on-target, inducible toxicity. Rapid clinical development of this method is promising as a new modality for treatment of pancreatic cancer. This article is protected by copyright. All rights reserved.
    Keywords:  lectin; pancreatic cancer; photoimmunotherapy; rBC2LCN; targeted therapy
    DOI:  https://doi.org/10.1002/ijc.34362
  3. ACS Nano. 2022 Nov 21.
    Multiplexed Organelles Portrait Barcodes for Subcellular MicroRNA Array Detection in Living Cells.
    Wei Wei, Huiting Lu, Wenhao Dai, Xiaonan Zheng, Haifeng Dong.
      Multiplexed profiling of microRNAs' subcellular expression and distribution is essential to understand their spatiotemporal function information, but it remains a crucial challenge. Herein, we report an encoding approach that leverages combinational fluorescent dye barcodes, organelle targeting elements, and an independent quantification signal, termed Multiplexed Organelles Portrait Barcodes (MOPB), for high-throughput profiling of miRNAs from organelles. The MOPB barcodes consist of heterochromatic fluorescent dye-loaded shell-core mesoporous silica nanoparticles modified with organelle targeting peptides and molecular beacon detection probes. Using mitochondria and endoplasmic reticulum as models, we encoded four Cy3/AMCA ER-MOPB and four Cy5/AMCA Mito-MOPB by varying the Cy3 and Cy5 intensity for distinguishing eight organelles' miRNAs. Significantly, the MOPB strategy successfully and accurately profiled eight subcellular organelle miRNAs' alterations in the drug-induced Ca2+ homeostasis breakdown. The approach should allow more widespread application of subcellular miRNAs and multiplexed subcellular protein biomarkers' monitoring for drug discovery, cellular metabolism, signaling transduction, and gene expression regulation readout.
    Keywords:  Ca2+ Homeostasis; Living Cell Imaging; MicroRNAs Detection; Multiplexed Barcode; Organelles Targeting; Subcellular Heterogeneity
    DOI:  https://doi.org/10.1021/acsnano.2c06252
  4. Adv Healthc Mater. 2022 Nov 21. e2202412
    Antitumor activity of anti-miR-21 delivered through lipid nanoparticles.
    Zhongkun Zhang, Yirui Huang, Jing Li, Fei Su, Jimmy Chun-Tien Kuo, Yingwen Hu, Xiaobin Zhao, Robert J Lee.
      The ability of lipid nanoparticles (LNPs) to deliver nucleic acids had shown a great therapeutic potential to treat a variety of diseases. Here, an optimized formulation of QTsome lipid nanoparticle (QTPlus) was utilized to deliver an anti-miR-21 (AM21) against cancer. The miR-21 downstream gene regulation and antitumor activity was evaluated using mouse and human cancer cells and macrophages. The antitumor activity of QTPlus encapsulating AM21 (QTPlus-AM21) was further evaluated in combination with erlotinib and atezolizumab (ATZ). QTPlus-AM21 demonstrated a superior miR-21-dependent gene regulation and eventually inhibited A549 non-small cell lung cancer growth in vitro. QTPlus-AM21 further induced chemo-sensitization of A549 cells to erlotinib with a combination index of 0.6 in inhibiting A549 cell growth. When systemically administered to MC38 tumor-bearing mouse model, QTPlus-AM21 exhibited an antitumor immune response with over 80% tumor growth inhibition (TGI%) and over 2-fold and 4-fold PD-1 and PD-L1 upregulation in tumors and spleens. The combination therapy of QTPlus-AM21 and ATZ further showed a higher antitumor response (TGI% over 90%) and successfully increased M1 macrophages and CD8 T cells into TME. This study provides new insights into the antitumor mechanism of AM21 and showed great promise of QTPlus-AM21 in combination with chemotherapies and immunotherapies. This article is protected by copyright. All rights reserved.
    Keywords:  Cancer Therapy; Immunoregulation; Lipid Nanoparticle; Oligonucleotide
    DOI:  https://doi.org/10.1002/adhm.202202412
  5. Nat Commun. 2022 Nov 22. 13(1): 7165
    Polymeric micelles effectively reprogram the tumor microenvironment to potentiate nano-immunotherapy in mouse breast cancer models.
    Myrofora Panagi, Fotios Mpekris, Pengwen Chen, Chrysovalantis Voutouri, Yasuhiro Nakagawa, John D Martin, Tetsuro Hiroi, Hiroko Hashimoto, Philippos Demetriou, Chryso Pierides, Rekha Samuel, Andreas Stylianou, Christina Michael, Shigeto Fukushima, Paraskevi Georgiou, Panagiotis Papageorgis, Petri Ch Papaphilippou, Laura Koumas, Paul Costeas, Genichiro Ishii, Motohiro Kojima, Kazunori Kataoka, Horacio Cabral, Triantafyllos Stylianopoulos.
      Nano-immunotherapy improves breast cancer outcomes but not all patients respond and none are cured. To improve efficacy, research focuses on drugs that reprogram cancer-associated fibroblasts (CAFs) to improve therapeutic delivery and immunostimulation. These drugs, however, have a narrow therapeutic window and cause adverse effects. Developing strategies that increase CAF-reprogramming while limiting adverse effects is urgent. Here, taking advantage of the CAF-reprogramming capabilities of tranilast, we developed tranilast-loaded micelles. Strikingly, a 100-fold reduced dose of tranilast-micelles induces superior reprogramming compared to free drug owing to enhanced intratumoral accumulation and cancer-associated fibroblast uptake. Combination of tranilast-micelles and epirubicin-micelles or Doxil with immunotherapy increases T-cell infiltration, resulting in cures and immunological memory in mice bearing immunotherapy-resistant breast cancer. Furthermore, shear wave elastography (SWE) is able to monitor reduced tumor stiffness caused by tranilast-micelles and predict response to nano-immunotherapy. Micellar encapsulation is a promising strategy for TME-reprogramming and SWE is a potential biomarker of response.
    DOI:  https://doi.org/10.1038/s41467-022-34744-1
  6. Nat Commun. 2022 Nov 23. 13(1): 7204
    Compact zinc finger base editors that edit mitochondrial or nuclear DNA in vitro and in vivo.
    Julian C W Willis, Pedro Silva-Pinheiro, Lily Widdup, Michal Minczuk, David R Liu.
      DddA-derived cytosine base editors (DdCBEs) use programmable DNA-binding TALE repeat arrays, rather than CRISPR proteins, a split double-stranded DNA cytidine deaminase (DddA), and a uracil glycosylase inhibitor to mediate C•G-to-T•A editing in nuclear and organelle DNA. Here we report the development of zinc finger DdCBEs (ZF-DdCBEs) and the improvement of their editing performance through engineering their architectures, defining improved ZF scaffolds, and installing DddA activity-enhancing mutations. We engineer variants with improved DNA specificity by integrating four strategies to reduce off-target editing. We use optimized ZF-DdCBEs to install or correct disease-associated mutations in mitochondria and in the nucleus. Leveraging their small size, we use a single AAV9 to deliver into heart, liver, and skeletal muscle in post-natal mice ZF-DdCBEs that efficiently install disease-associated mutations. While off-target editing of ZF-DdCBEs is likely too high for therapeutic applications, these findings demonstrate a compact, all-protein base editing research tool for precise editing of organelle or nuclear DNA without double-strand DNA breaks.
    DOI:  https://doi.org/10.1038/s41467-022-34784-7
  7. J Control Release. 2022 Nov 19. pii: S0168-3659(22)00767-2. [Epub ahead of print]
    Optimization of storage conditions for lipid nanoparticle-formulated self-replicating RNA vaccines.
    Byungji Kim, Ryan R Hosn, Tanaka Remba, Dongsoo Yun, Na Li, Wuhbet Abraham, Mariane B Melo, Manuel Cortes, Bridget Li, Yuebao Zhang, Yizhou Dong, Darrell J Irvine.
      The recent clinical success of multiple mRNA-based SARS-CoV-2 vaccines has proven the potential of RNA formulated in lipid nanoparticles (LNPs) in humans, and products based on base-modified RNA, sequence-optimized RNA, and self-replicating RNAs formulated in LNPs are all in various stages of clinical development. However, much remains to be learned about critical parameters governing the manufacturing and use of LNP-RNA formulations. One important issue that has received limited attention in the literature to date is the identification of optimal storage conditions for LNP-RNA that preserve long-term activity of the formulations. Here, we analyzed the physical structure, in vivo expression characteristics, and functional activity of alphavirus-derived self-replicating RNA (repRNA)-loaded LNPs encoding HIV vaccine antigens following storage in varying temperatures, solvents, and in the presence or absence of cryoprotectants. We found that for lipid nanoparticles with compositions similar to clinically-used LNPs, storage in RNAse-free PBS containing 10% (w/vol) sucrose at -20 °C was able to maintain vaccine stability and in vivo potency at a level equivalent to freshly prepared vaccines following 30 days of storage. LNP(repRNA) could also be lyophilized with retention of bioactivity.
    Keywords:  Freeze-storage; Lipid nanoparticle; Lyophilization; RNA delivery; Vaccine storage
    DOI:  https://doi.org/10.1016/j.jconrel.2022.11.022
  8. Small. 2022 Nov 24. e2205260
    Platelet Membrane Cloaked Nanotubes to Accelerate Thrombolysis by Thrombus Clot-Targeting and Penetration.
    Bin Liu, Francesca Victorelli, Yu Yuan, Yi Shen, Hui Hong, Guohua Hou, Shuang Liang, Zekun Li, Xin Li, Xindi Yin, Fazheng Ren, Yuan Li.
      Thrombotic diseases have a high rate of mortality and disability, and pose a serious threat to global public health. Currently, most thrombolytic drugs especially protein drugs have a short blood-circulation time, resulting in low thrombolytic efficiency. Therefore, a platelet membrane (Pm) cloaked nanotube (NT-RGD/Pm) biomimetic delivery system with enhanced thrombolytic efficiency is designed. Nanotubes (NT) with an excellent clot-penetration properties are used to load a protein thrombolytic drug urokinase (Uk). Platelet-targeting arginine glycine-aspartic peptide (RGD) is grafted onto the surface of the nanotubes (NT-RGD) prior to cloaking. Multiple particle tracking (MPT) technique and confocal laser scanning microscope (CLSM) analysis are applied and the results show that the nanotubes possess a strong penetration and diffusion capacity in thrombus clots. After the Pm cloaking on NT-RGD/Uk, it shows a thrombus microenvironmental responsive release property and the half-life of Uk is six times longer than that of free Uk. Most importantly, NT-RGD-Uk/Pm exhibits a 60% thrombolytic efficiency in the FeCl3 -induced thrombosis mouse model, and it is able to significantly reduce the bleeding side effects of Uk. This Pm-cloaked nanotube system is an effective and promising platform for the controlled and targeted delivery of drugs for the thrombus treatment.
    Keywords:  drug delivery; nanotubes; platelet membranes; targeted accelerating thrombolysis; urokinase
    DOI:  https://doi.org/10.1002/smll.202205260
  9. J Control Release. 2022 Nov 17. pii: S0168-3659(22)00776-3. [Epub ahead of print]
    Reversible covalent nanoassemblies for augmented nuclear drug translocation in drug resistance tumor.
    Chun-Nan Zhu, Mei-Yu Lv, Fei Song, Dong-Yun Zheng, Chao Liu, Xiao-Jun Liu, Dong-Bing Cheng, Zeng-Ying Qiao.
      The drug efflux by P-glycoprotein (P-gp) is the primary contributor of multidrug resistance (MDR), which eventually generates insufficient nuclear drug accumulation and chemotherapy failure. In this paper, reversible covalent nanoassemblies on the basis of catechol-functionalized methoxy poly (ethylene glycol) (mPEG-dop) and phenylboronic acid-modified cholesterol (Chol-PBA) are successfully synthesized for delivery of both doxorubicin (DOX, anti-cancer drug) and tariquidar (TQR, P-glycoprotein inhibitor), which shows efficient nuclear DOX accumulation for overcoming tumor MDR. Through naturally forming phenylboronate linkage in physiological circumstances, Chol-PBA is able to bond with mPEG-dop. The resulting conjugates (PC) could self-assemble into reversible covalent nanoassemblies by dialysis method, and transmission electron microscopy analysis reveals the PC distributes in nano-scaled spherical particles before and after drug encapsulation. Under the assistance of Chol, PC can enter into lysosome of tumor cells via low-density lipoprotein (LDL) receptor-mediated endocytosis. Then the loaded TQR and DOX are released in acidic lysosomal compartments, which inhibit P-gp mediated efflux and elevate nuclear accumulation of DOX, respectively. At last, this drug loaded PC nanoassemblies show significant tumor suppression efficacy in multidrug-resistant tumor models, which suggests great potential for addressing MDR in cancer therapy.
    Keywords:  Drug delivery; Multidrug resistance; Nanoassemblies; Phenylboronate
    DOI:  https://doi.org/10.1016/j.jconrel.2022.11.031
  10. Nano Lett. 2022 Nov 21.
    Biomimetic Microadhesion Guided Instant Spinning.
    Zhuxi Ni, Zhiwei Zhu, Yuan Ji, Xuewei He, Xuewei Fu, Wei Yang, Yu Wang.
      Animals create high-performance fibers at natural ambient conditions via a unique spinning process. In contrast, the spinning technologies developed by human beings are usually clumsy and require sophisticated skills. Here, inspired by adhesion-based silkworm spinning, we report a microadhesion guided (MAG) spinning technology for instant and on-demand fabrication of micro/nanofibers. Enabled by the adhesion between the spinning fluids and the microneedles, the MAG spinning can generate micro/nanofibers with programmable morphology. By further mimicking the head movement of the silkworm spinning, the MAG technology is extended with three different modes: straight, vibratory, and twisted spinning, which generate oriented fibers, hierarchical cross-linked fibers, and all-in-one fibers, respectively. Due to the prevalence of microadhesion and its unprecedented flexibility in operation, equipment-free MAG spinning is finally realized for instant fiber fabrication by only polymeric foams. Finally, the MAG spinning is demonstrated as a promising instant technology for emergent applications, such as wound dressing.
    Keywords:  Bioinspired and biomimetic polymer processing; biomedical engineering; equipment-free spinning and microfluidics; microadhesion guided instant technology; silkworm and spider fiber
    DOI:  https://doi.org/10.1021/acs.nanolett.2c03297
  11. Science. 2022 Nov 25. 378(6622): 858-864
    Engineering bacteria as interactive cancer therapies.
    Candice R Gurbatri, Nicholas Arpaia, Tal Danino.
      With increasing evidence that microbes colonize tumors, synthetic biology tools are being leveraged to repurpose bacteria as tumor-specific delivery systems. These engineered systems can modulate the tumor microenvironment using a combination of their inherent immunogenicity and local payload production. Here, we review genetic circuits that enhance spatial and temporal control of therapeutic bacteria to improve their safety and efficacy. We describe the engineering of interactions among bacteria, tumor cells, and immune cells, and the progression from bacteria as single agents toward their rational combination with other modalities. Together, these efforts are building toward an emerging concept of engineering interactions between programmable medicines using synthetic biology.
    DOI:  https://doi.org/10.1126/science.add9667
  12. J Control Release. 2022 Nov 21. pii: S0168-3659(22)00772-6. [Epub ahead of print]353 30-41
    Size-switchable polymer-based nanomedicines in the advanced therapy of rheumatoid arthritis.
    A Libánská, E Randárová, S Skoroplyas, M Bartoš, J Luňáčková, F Lager, G Renault, D Scherman, T Etrych.
      Chronic inflammatory diseases such as rheumatoid arthritis represent a substantial socio-economic impact and have a high prevalence in the modern world. Nano-sized polymer therapeutics have shown suitable characteristics for becoming the next generation of anti-inflammatory nanomedicines. Here, we present biocompatible and stimuli-sensitive N-(2-hydroxypropyl)methacrylamide based polymer conjugates with the anti-inflammatory drug dexamethasone (DEX), which has been tailored for prolonged blood circulation, enhanced inflammatory site accumulation, site-specific drug release and subsequent elimination of the carrier via urine excretion. The hydrodynamic size of novel polymer-DEX nanomedicine was adjusted to prolong its blood circulation whilst maintaining the renal excretability of the polymer carrier after drug release in inflamed tissue. The therapeutic efficacy of the studied polymer nanomedicines was evaluated in a model of dissipated chronic arthritis, i.e. collagen II-induced arthritis, in mice. The pH-sensitive drug attachment enabled enhanced blood circulation with minimal systemic drug release, as well as rapid drug activation in affected joints. Importantly, unlike free DEX, the polymer nanomedicines were able to diminish joint inflammation and arthritis-induced bone damage - even at a reduced dosing regimen - as evaluated by micro computed tomography (micro-CT).
    Keywords:  Collagen II-induced arthritis; Dexamethasone; Drug delivery; HPMA; Inflammation; Passive targeting; Polymer conjugate
    DOI:  https://doi.org/10.1016/j.jconrel.2022.11.027
  13. Adv Mater. 2022 Nov 22. e2207282
    Self-healing electronics for prognostic monitoring of methylated circulating tumor DNAs.
    Peilin Fang, Xianglin Ji, Xi Zhao, Richard Yan Do, Youyang Wan, Ying Wang, Yuanting Zhang, Peng Shi.
      Methylated circulating DNAs (ctDNAs) have recently been reported as a promising biomarker for early cancer diagnostics, but limited tools are currently available for continuous and dynamic profiling of ctDNAs and their methylation levels, especially when such assays need to be conducted in point-of-care (POC) scenarios. Here, we developed a self-healing bioelectronic patch (iMethy) that combines transdermal interstitial fluid (ISF) extraction and field effect transistor-based (FET-based) biosensing for dynamic monitoring of methylated ctDNAs as a prognostic approach for cancer risk management. The projection micro-stereolithography-based 3D patterning of an EGaIn circuit with an unprecedented 10 μm resolution enables the construction of self-healing Eutectic Gallium-Indium microfluidic circuits that remain conductive under 100% strain and self-healing under severe destruction. In combination with continuous transdermal ISF sampling of methylated ctDNAs, iMethy can detect ctDNAs as low as 10-16  M in cellular models and is capable of phenotypic analysis of tumor growth in rodent animals. As the first demonstration of a wearable device for real-time in vivo analysis of disease-indicative biomarkers, this proof-of-concept study well demonstrated the potential of the iMethy platform for cancer risk management based on dynamic transdermal surveillance of methylated ctDNAs via a painless and self-administrable procedure. This article is protected by copyright. All rights reserved.
    Keywords:  cancer diagnostics; circulating tumor DNA; epigenetic regulation; self-healing electronics; smart biosensing; wearable devices
    DOI:  https://doi.org/10.1002/adma.202207282
  14. Nat Commun. 2022 Nov 22. 13(1): 7166
    Functionally integrating nanoparticles alleviate deep vein thrombosis in pregnancy and rescue intrauterine growth restriction.
    Juan Cheng, Siqi Zhang, Chenwen Li, Ke Li, Xiaoyan Jia, Quanfang Wei, Hongbo Qi, Jianxiang Zhang.
      There is still unmet demand for effective, safe, and patient-friendly anti-thrombotics to treat deep vein thrombosis (DVT) during pregnancy. Here we first engineer a bioactive amphiphile (TLH) by simultaneously conjugating Tempol and linoleic acid onto low molecular weight heparin (LMWH), which can assemble into multifunctional nanoparticles (TLH NP). In pregnant rats with DVT, TLH NP can target and dissolve thrombi, recanalize vessel occlusion, and eradicate the recurrence of thromboembolism, thereby reversing DVT-mediated intrauterine growth restriction and delayed development of fetuses. Mechanistically, therapeutic effects of TLH NP are realized by inhibiting platelet aggregation, facilitating thrombolysis, reducing local inflammation, attenuating oxidative stress, promoting endothelial repair, and increasing bioavailability. By decorating with a fibrin-binding peptide, targeting efficiency and therapeutic benefits of TLH NP are considerably improved. Importantly, LMWH nanotherapies show no toxicities to the mother and fetus at the dose 10-time higher than the examined therapeutic dosage.
    DOI:  https://doi.org/10.1038/s41467-022-34878-2
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