nature medicine research paper

Nature Medicine

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• Biochemistry, Genetics and Molecular Biology (miscellaneous)
• Medicine (miscellaneous)

Nature Research

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10788956, 1546170X

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[email protected]

The set of journals have been ranked according to their SJR and divided into four equal groups, four quartiles. Q1 (green) comprises the quarter of the journals with the highest values, Q2 (yellow) the second highest values, Q3 (orange) the third highest values and Q4 (red) the lowest values.

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Nature medicine: mrna nanomedicine.

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Messenger RNA (mRNA) is an emerging class of therapeutic agent for the prevention and treatment of a wide range of diseases, including COVID-19. We present the latest advances and innovations in the growing field of mRNA nanomedicine for ongoing clinical translation and future clinical directions.

Read the paper

The landscape of mRNA nanomedicine - Nature Medicine

The COVID-19 mRNA vaccines have transformed the field of mRNA nanomedicine, but this new class of therapeutics has the potential to treat many other diseases. This Review profiles the latest advances and challenges.

Challenges related to mRNA stability and immunogenicity, as well as in vivo delivery and the ability to cross multiple biological barriers, have been largely addressed by recent progress in mRNA engineering and delivery. 

mRNA nanomedicines have already shown efficacy as vaccines for the prevention of COVID-19 and reducing the risk of hospitalization and death 3 , 27 , 28 , 29 . Encouraged by this success, more and more mRNA-based vaccines and therapies are expected to reach clinical translation. However, several crucial goals must be reached before the potential of mRNA nanomedicines is fully realized. Increasing evidence suggests that specific biological pathways may interfere with mRNA delivery or translation 195 , 196 . Thus, understanding how biological pathways affect in vivo mRNA delivery and translation can further improve the efficacy of mRNA drugs, while the potential toxicity and immune response raised by mRNAs and their carriers should also be carefully considered.

Ultimately, the quick and efficient implementation of mRNA nanomedicines depends largely on their stability and logistical requirements, which impact real-world implementation and rollout. Therefore, innovations that improve stability will be crucial. In recent studies, a thermostable mRNA vaccine was reported to provide protective efficacy against SARS-CoV-2 in mice 197   and entered clinical trials 198 . Moderna’s next-generation COVID-19 vaccine mRNA-1283 could be stable at 2–5 °C.

New engineering advanaces will facilitate real-world applications of mRNA nanomedicines in myriad ways. For example, novel PLGA microparticles could be a promising platform for mRNA delivery with programable drug release and even enable self-boosting vaccines 199 , 200 , 201 . In addition, microneedle patches, which have demonstrated their safety and immunogenicity as carriers for seasonal influenza 202   and SARS-CoV-2 (refs.   203 , 204 ) vaccines, could be a convenient and minimally invasive platform for mRNA delivery.

Since the enormous potential of mRNA nanomedicines has already been demonstrated by the unprecedented mRNA COVID-19 vaccines, we expect that continued innovation will lead to new and highly efficient mRNA-based therapies, including vaccines for other non-COVID-19 infectious diseases, cancer immunotherapy, protein therapy, gene-editing-based therapy and potentially many others.

Related reading: https://orcid.org/0000-0001-7114-1095   

https://www.nature.com/articles/s41591-022-02061-1

https://www.nature.com/articles/s41565-022-01174-5

https://www.nature.com/articles/s41467-022-28744-4

https://www.nature.com/articles/s41565-021-01040-w

https://www.nature.com/articles/s41467-021-25075-8

https://www.nature.com/articles/s41467-021-24961-5

https://www.nature.com/articles/s41467-021-21436-5   

https://www.nature.com/articles/s41578-020-00247-y 

https://www.nature.com/articles/s41467-019-12462-5

https://bioengineeringcommunity.nature.com/posts/tackling-covid-19-with-materials-science   https://bioengineeringcommunity.nature.com/posts/micropatterned-microfluidics-dendronized-fluorosurfactants-for-highly-stable-emulsions https://bioengineeringcommunity.nature.com/posts/nature-derived-2-dimensional-materials-for-cancer-therapy-and-sustainable-solutions https://bioengineeringcommunity.nature.com/posts/multi-targeted-reactive-oxygen-species-burst-for-cancer-therapy

https://bioengineeringcommunity.nature.com/posts/aladdin-magic-mat-non-printed-integrated-circuit-textile-for-wireless-theranostics

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• D Gao, T Chen, Y Han, S Chen, Y Wang, X Guo, H Wang, X Chen, M Guo, Y Zhang, G Hong,   X Zhang* , Z Tian*, Z Yang*. Targeting Hypoxic Tumors with Hybrid Nanobullets for Oxygen-independent Synergistic Photothermal-thermodynamic Therapy.   Nano-Micro Letters , 2021,13, 99. ( Featured Cover Paper )
• Y Yang, X Wei, N Zhang*, J Zheng, Q Wen, X Luo, C Lee, X Liu,   X Zhang *, J Chen, C Tao, W Zhang*, X Fan*. A non-printed integrated-circuit textile for wireless theranostics.   Nature Communications .   2021, 12, 4876.
• X Ji, L Ge, C Liu, Z Tang, Y Xiao, Z Lei, W Gao, S Blake, D De, X Zeng, N Kong,*   X Zhang*,   W Tao*. Capturing functional two-dimensional nanosheets from sandwich-structure vermiculite: synthesis and application in cancer theranostics.   Nature   Communications , 2021, 12, 1124.
• N Kong, H Zhang, C Feng, C Liu, Y Xiao,   X Zhang , L Mei, J S Kim, W Tao, X Ji. Arsenene-mediated multiple independently targeted reactive oxygen species burst for cancer therapy.   Nature Communications.   2021, 12, 4777.
• Z Tang†, N Kong†,  X. Zhang†,  Y Liu, P Hu, S Mou, P Liljeström, J Shi, W Tan, J S Kim, Y Cao, R Langer,  K W. Leong, O C. Farokhzad, W Tao. A materials-science perspective on tackling COVID-19.  Nature Reviews Materials , 2020, 5, 847-860. ( Featured  Cover Paper ,  highly cited paper, accessed>20,000 times) 
• J Li, S Song, J Meng, Z Li,  X Liu*, L Tan, Y Zheng, C Li, K Yeung, Z Cui, Y Liang, S Zhu,  X Zhang* , S Wu*. 2D MOF periodontitis photodynamic ion therapy.  Journal of the American Chemical Society ,  2021, 143, 37, 15427-15439. ( Selected for“ A Virtual Issue on Nanomedicine” collection papers from ACS Nano and JACS)
• Y Wang, D Gao, Y Liu, X Guo, S Chen, L Zeng, J Ma,   X Zhang* , Z Tian*, Z Yang*. Immunogenic-Cell-Killing and Immunosuppression-Inhibiting Nanomedicine.   Bioactive Materials , 2020, 6 (6), 1513-1527.
• J Yang†,   X Zhang† , C Liu†, Z Wang, L Deng, C Feng, W Tao, X Xua, W Cui. Biologically Modified Nanoparticles as Theranostic   Progress in Materials Science , 2021, 118, 100768.
• Z Yang, D Gao, X Guo, L Jin, J Zhang, Y Wang, S Chen, X Zheng, L Zeng, M Guo,   X Zhang* , Z Tian*. Fighting immune cold and reprogramming immunosuppressive tumor microenvironment with red blood cell membrane-camouflaged   ACS Nano , 2020, 14, 12, 17442-17457.
• D Wei, Y Yu, Y Huang,1 Y Jiang, Y Zhao, Z Nie, F Wang, W Ma, Z Yu, Y Huang, X Zhang, Z Liu,   X Zhang , H Xiao. A Near-Infrared-II Polymer with Tandem Fluophores Demonstrates Superior Biodegradability for Simultaneous Drug Tracking and Treatment Efficacy Feedback.   ACS Nano , 2021, 15 (3), 5428–5438.
• D Wei, Y Yu,   X Zhang , Y Wang, H Chen, Y Zhao, F Wang, G Rong, W Wang, X Kang, J Cai, Z Wang, J Yin, M Hanif, Y Sun, G Zha, L Li, G Nie, H Xiao*. Breaking down the intracellular redox balance with diselenium nanoparticles for maximizing chemotherapy efficacy on patient-derived xenograft models.   ACS Nano , 2020, 14, 12, 16984-16996.
• Z Lei, W Zhu,   X Zhang , X Wang, P Wu. Bio-inspired ionic skin for theranostics hydrogel.  Advanced   Functional Materials ,  2020, 2008020.
• D Gao, X Guo,   X Zhang* , S Chen, Y Wang, T Chen, G Huang, Y Gao, Z Tian*, Z Yang*. Multifunctional phototheranostic nanomedicine for cancer imaging and treatment.   Materials   Today Bio . 2019, 5,100035. ( Invited Paper ,   ESI highly cited paper , open access with a fee waiver, 99.983% excellence,   2 nd   most highly cited paper   of   Materials Today Bio )
• J Ouyang†, X Ji†,   X Zhang†,   C Feng, Z Tang, N Kong, A Xie, J Wang, X Sui, L Deng, Y Liu, J S Kim, Y Cao, W Tao*. In situ sprayed NIR-responsive, analgesic black phosphorus-based gel for diabetic ulcer   Proceedings of the National Academy of Sciences of the United States of America   ( PNAS ) , 2020, 117 (46), 28667-28677. ( highly cited paper ,   Highlighted by: MRS Bulletin Materials News)
• G Parekh, Y Shi, J Zheng,   X Zhang* , S Leporatti. Nano-carriers for targeted delivery and biomedical imaging enhancement.   Therapeutic Delivery , 2018, 9(6), 451-468.
•  C Liu, S Sun, Q Feng, Y Wu, N Kong, Z Yu, J Yao,   X Zhang , W Chen, Z Tang,  Y Xiao, X Huang, A Lv, Y Cao, A Wu, T Xie, W Tao. Arsenene Nanodots with Selective Killing Effects and their Low‐Dose Combination with ß‐Elemene for Cancer Therapy.   Advanced Materials , 33(37) (2021) 2102054.
• W Y Kim, M Won, S Koo,   X Zhang , J S Kim. Mitochondrial H2Sn-Mediated Anti-Inflammatory Theranostics.   Nano-Micro Letters,    2021, 13, 168.

Other Related   Nature-derived/inspired   materials/tea   works:

• C Liu, S Sun, Q Feng, Y Wu, N Kong, Z Yu, J Yao,   X Zhang , W Chen, Z Tang,  Y Xiao, X Huang, A Lv, Y Cao, A Wu, T Xie, W Tao. Arsenene Nanodots with Selective Killing Effects and their Low‐Dose Combination with ß‐Elemene for Cancer Therapy.   Advanced Materials , 33(37) (2021) 2102054.
• Y Xie, J Yin, J Zheng, L Wang, J Wu, M Dresselhaus,   X Zhang* . Synergistic cobalt sulfide/eggshell membrane carbon   ACS   Applied   Materials   & Interfaces . 2019, 11 (35), 32244-32250.
• X Ji, L Ge, C Liu, Z Tang, Y Xiao, Z Lei, W Gao, S Blake, D De, X Zeng, N Kong*,   X Zhang*,   W Tao*. Capturing functional two-dimensional nanosheets from sandwich-structure vermiculite: synthesis and application in cancer theranostics.   Nature   Communications , 2021,12,1124.
• Z Li, D Chu, Y Gao, L Jin*,   X Zhang* , W Cui, J Li*. Biomimicry, biomineralization, and bioregeneration of bone using advanced three-dimensional fibrous hydroxyapatite   Materials   Today Advances . 2019,3,100014. (Invited open-access paper among  most highly cited paper   of   Materials Today Advances )
• L Jin, J Li, L Liu*, Z Wang*,   X Zhang* . Facile synthesis of carbon dots with superior sensing.   Applied Nanoscience , 2018, 755(3), 1-8.
• Y Wang, L Lu, G Zheng*,   X Zhang* . Microenvironment-controlled micropatterned microfluidic model for biomimetic in-situ studies.   ACS Nano , 2020, 14(8), 9861-9872. ( Featured   Cover Paper )
• Z Li†,   X Zhang† , Z Guo, L Shi, L Jin, L Zhu, X Cai, J Zhang, Y Liu, Y Zhang, J Li. Nature-Derived Bionanomaterials for sustained release of 5-fluorouracil to inhibit subconjunctival fibrosis.   Materials Today Advances , 2021, 11, 100150.  
• X Chen, Y Chen, L Zou,   X Zhang,   Y Dong, J Tang, D McClements, W Liu. Plant-based Nanoparticles Consisting of a Protein Core and Multilayer Phospholipid Shell: Fabrication, Stability, and    Journal   of Agricultural and Food Chemistry , 2019, 67 (23), 6574-6584.
• P Tang, D Shen, Y Xu,   X Zhang* , J Shi, J Yin*. Effect of fermentation conditions and the tenderness of tea leaves on the chemical components and sensory quality of fermented juice.   Journal of Chemistry , 2018, 4312875,1-7.
• X Zhang* . Tea and cancer prevention.   Journal   of Cancer Research Updates , 2015, 4 (2), 65-73.
• Q Zhang, W Li, K Li, H Nan, C Shi, Y Zhang, Z Dai, Y Lin, X Yang, Y Tong, D Zhang, C Lu, L Feng, C Wang, X Liu, J Huang, W Jiang, X Wang,   X Zhang , Eichler, Z. Liu, L. Gao. The Chromosome-Level Reference Genome of Tea Tree Unveils Recent Bursts of Non-autonomous LTR Retrotransposons in Driving Genome Size Evolution.   Molecular plant   2020,13 (7), 935-938.
• Y Yang†, P Jin†,   X Zhang† , N Ravichandran, H Ying, C Yu, H Ying, Y Xu, J Yin, K Wang, M Wu, Q New epigallocatechin gallate (EGCG) nanocomplexes co-assembled with 3-mercapto-1-hexanol and ß- lactoglobulin for improvement of antitumor activity.   Journal of Biomedical Nanotechnology , 2017,13 (7), 805-814.
• X Zhang* , G Parekh, B Guo, X Huang, Y Dong, W Han, X Chen, G Polyphenol and Self-Assembly: Metal Polyphenol Nanonetwork for Drug Delivery and Biomedical Applications.   Future Drug Discovery , 2019, 1 (1), FDD7. ( Invited   open-access paper with a fee waiver,   most cited paper   of the journal)

Related   2-dimentional/carbon materials  works:

• Y Zheng, H Wei, P Liang, X Xu, X Zhang, H Li, C Zhang, C Hu,   X Zhang , B Lei, W Wong, Y Liu, J Zhuang. Near-infrared-excited multicolor afterglow in carbon dots-based room-temperature phosphorescent materials.   Angewandte Chemie ,   2021, 202108696.  
• G Li, C Liu, X Zhang, P Luo, G Lin, W Jiang. Highly photoluminescent carbon dots-based immunosensors for ultrasensitive detection of aflatoxin M1 residues in milk. Food Chemistry. 2021, 355, 129443.
• L Jin, X Guo, D Gao, G Tan, N Du, X Wang, Y Zhang, Z Yang*,   X Zhang*.   NIR-responsive MXene nanobelts for wound   NPG Asia Materials . 2021,13, 24. Selected for the “Special Issue on Biomaterials and Health-care related Materials”.
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• J Cui, J Yin, J Zheng, J Meng, M Liao, T Wu, S He, S Wei, Z Xie, H Wang, M Dresselhaus, Y Xie*, J Wu*,  C Lu*,   X Zhang*.   Supermolecule cucurbituril subnanoporous carbon supercapacitor(SCSCS).   Nano Letters ,   2021, 21 (5), 2156–2164.
• J Meng, Z Liu, X Liu, W Yang, L Wang, Y Li, Y Cao,   X Zhang* , L Mai*. Scalable fabrication and active site identification of MOF shell-derived nitrogen-doped carbon hollow frameworks for oxygen   Journal of Materials Science & Technology , 2020, 66, 186-192.
• F Han, S Lv, Z Li, L Jin, B Fan*, J Zhang, R Zhang,   X Zhang* , L Han, J Li*. Triple-synergistic 2D material- based dual-delivery antibiosis platform.   NPG Asia Materials , 2020,12,15.
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• X Ji, L Ge, C Liu, Z Tang, Y Xiao, Z Lei, W Gao, S Blake, D De, X Zeng, Na Kong*,   X Zhang*,   W Tao*. Capturing functional two-dimensional nanosheets from sandwich-structure vermiculite: synthesis and application in cancer theranostics.   Nature   Communications , 2021, 12, 1124.
• X Ji, L Ge, C Liu, Z Tang, Y Xiao, Z Lei, W Gao, S Blake, D De, X Zeng, Na Kong*,   X Zhang*,   W Tao*. Capturing functional two-dimensional nanosheets from sandwich-structure vermiculite: synthesis and application in cancer theranostics.   Nature   Communications , 2021, 12, 4777.
• J Meng, Q He, L Xu,   X Zhang , F Liu, X Wang, Q Li, X Xu, G Zhang, C Niu, Z Identification of phase control of carbon-confined Nb2O5 nanoparticles towards high-performance lithium  storage.    Advanced Energy Mat erials , 2019, 9 (18), 1802695.
• J Wu, F Xu, S Li, Q, Liu,   X Zhang , Q Liu, R Fu, D Wu. Porous polymers as multifunctional material platforms toward task‐specific applications.   Advanced  Materials ,   2019,  31(4),  1802922.  (Citation>145,   ESI Highly Cited Paper , Invited Paper)
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MXene composite nanofibers for cell culture and tissue engineering.   ACS Applied Bio Materials . 2020, 3(4), 2125-2131.  

J Ouyang, C Feng, X Zhang, N, Kong, W. Tao. Black Phosphorus in Biomedical applications: Evolutionary Journey from Monoelemental Materials to Composite Materials.   Accounts of Materials Research.   2021, 2, 7, 489–500 .  ( Featured  Cover Paper ,   ACS Editors` Choice ,  chosen from the entire ACS portfolio).

Related micropatterned microfluidics studies:

1） https://www.nature.com/articles/s41578-020-00247-y

Imaging systems and microfluidic devices for the in-depth and real-time investigation of viral structures and transmission，material platforms for organoids and organs-on-a-chip, in drug delivery and vaccination, and for the production of medical equipment.

• Z Tang†, N Kong†, X   Zhang†,   Y Liu, P Hu, S Mou, P Liljeström, J Shi, W Tan, J S Kim, Y Cao, R Langer, K W. Leong, O C. Farokhzad, W Tao. A materials-science perspective on tackling COVID-19.   Nature Reviews Materials , 2020, 5, 847-860. ( Featured   Cover Paper ,   highly cited paper, accessed>19,000 times , Impact Factor:71.189)

  2）https://www.nature.com/articles/s41467-019-12462-5

Dendronized fluorosurfactant for highly stable water-in-fluorinated oil emulsions with minimal inter-droplet transfer of small molecules

• M Chowdhury, W Zheng, S Kumari, J Heyman,   X Zhang,   P Dey, D Weitz, R Haag. Dendronized fluorosurfactants provide phenomenal droplet integrity to picolitre emulsions for therapeutics development.   Nature Communications , 2019, 10, 4546 (Impact Factor:14.919).

3)   https://doi.org/10.1021/acsnano.0c02701

An osmotic-pressure, pH, excretion, nutrition, gas, ionic-strength, flow-rate, and temperature (OPEN GIFT) microenvironment-controlled micropatterned microfluidic model (MMMM) for biomimetic in situ studies (BISS) in simulating the  in vivo  microenvironment to study  in situ  the stress applied to  Giardia  in the intestinal tract. 

• Y Wang, L Lu, G Zheng*,   X Zhang* . Microenvironment-controlled micropatterned microfluidic model for biomimetic in-situ studies.   ACS Nano , 2020, 14(8), 9861-9872. ( Featured   Cover Paper,   Impact Factor:15.881).

4) https://doi.org/10.1016/j.bios.2019.111597

• S Han†, Q Zhang†,   X Zhang†,   X Liu, L Lu, J Wei, Y Li, Y Wang, G A digital microfluidic diluter- based microalgal motion biosensor for marine pollution monitoring.   Biosensors and Bioelectronics , 2019, 143, 111957 (Impact Factor:10.257).

5)    https://doi.org/10.2144/btn-2019-0134 

• L Liu, N Xiang, Z Ni, X Huang, J Zheng, Y Wang,   X Zhang* . Step Emulsification: High throughput production of monodisperse droplets.   BioTechniques , 2020, 68 (3), 114-116. ( Invited Expert Paper )

6)  https://doi.org/10.1016/j.nantod.2021.101152    https://authors.elsevier.com/a/1cv~x6DSyB6RP5

•  S Wang, Z Shen, Z Shen, Y Dong, Y Li, Y Cao, Y Zhang, S Guo, J Shuai, Y Yang, C Lin, M Guo, X Chen*, X Zhang*, Q Huang*. Machine-learning micropattern manufacturing.   Nano Today , 2021, 38 (2021), 101152. (Impact Factor:20.722)

7)  https://doi.org/10.1016/j.bioactmat.2021.04.014

• Z Li†,   X Zhang†   J Ouyang, D Chu, F Han, L Shi, R Liu, Z Guo, G Gu, W Tao, L Jin, J Li. Ca 2+ -supplying black phosphorus-based scaffolds developed with microfluidic technology for osteogenesis.   Bioactive materials , 2021, 6(11), 4053-4064. (Instant   Impact Factor:14.093).          

8)  https://doi.org/10.1016/j.pmatsci.2020.100768  

Microfluidic technology for Theranostics.

• J Yang†,   X Zhang† , C Liu†, Z Wang, L Deng, C Feng, W Tao, X Xua, W Cui. Biologically Modified Nanoparticles as Theranostic Bionanomaterials.   Progress in Materials Science , 2021, 118, 100768. (Impact Factor:39.58)

9)  https://doi.org/10.1007/s40820-021-00663-x

• M Chowdhury†,   X Zhang † ,   L Amini, A Faghani, A Singh, M Henneresse, R Haag. Functional Surfactants for Molecular Fishing, Capsule Creation, and Single-Cell Gene Expression.  Nano-Micro Letters, 2021, 13, 147. (Impact Factor:16.419)

  10)  https://doi.org/10.1021/acs.analchem.1c00917

  1.  G Zheng, Q Gao, Y Jiang, L Lu, J Li， X Zhang , H Zhao, P Fan, Y Cui, F Gu, Y Wang.            Instrumentation-compact digital microfluidic (DMF) reaction interface extended  loop-mediated isothermal amplification (LAMP) for sample-to-answer testing of Vibrio parahaemolyticus.  Analytical Chemistry, 2021, 93, 28, 9728–9736.

11)  https://doi.org/10.1016/j.marpolbul.2019.04.063   https://doi.org/ 10.1166/jnn.2019.16752    https://doi.org/10.1109/ICSENS.2010.5690979.

• Zhang, Q., Zhang, X., Zhang, X., Jiang, L., Yin, J., Zhang, P., Han, S., Wang, Y.& Zheng, G. A feedback-controlling digital microfluidic fluorimetric sensor device for simple and rapid detection of mercury (II) in costal seawater.  Marine pollution bulletin , 2019, 144, 20-27.    https://doi.org/10.1016/j.marpolbul.2019.04.063
• R Yang, Z Gong, X Zhang, L Que. Single-walled carbon nanotubes (SWCNTs) and poly(3,4- ethylenedioxythiophene) nanocomposite microwire-based electronic biosensor fabricated  by  microlithography and layer-by-layer nanoassembly.  Journal  of  Nanoscience  and  Nanotechnology , 2019,19(12), 7591-7595.  https://doi.org/ 10.1166/jnn.2019.16752  

Dr. Xingcai Zhang, Harvard/MIT Research Fellow; Science Writer/Editorial (Advisory) Board Member for Springer Nature, Materials Today, Royal Society of Chemistry, Wiley; with 5 STEM degrees/strong background in sustainable Nature-derived/inspired/mimetic materials for biomed/sensing/catalysis/energy/environment applications, with more than 100 high-impact journal publications in Nature Reviews Materials, Nature Nanotechnology, Nature Medicine, etc.   https://scholar.google.com/citations?hl=en&user=2vDraMoAAAAJ&view_op=list_works&sortby=pubdate

https://orcid.org/0000-0001-7114-1095

Contact: Dr. Xingcai Zhang [email protected]  [email protected] +1-2253041387 wechat:drtea1

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Xingcai Zhang (He/Him)

Harvard/MIT Research Fellow, Harvard University

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This journal encompasses original research ranging from new concepts in human biology and disease pathogenesis to new therapeutic modalities and drug development, to all phases of clinical work, as well as innovative technologies aimed at improving human health.

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Most Influential NATURE MEDICINE Papers (2022-02)

Nature Medicine is a monthly peer-reviewed medical journal publishing research articles, reviews, news and commentaries in the biomedical area, including both basic research and early-phase clinical research covering all aspects of medicine. Paper Digest Team analyze all papers published on NATURE MEDICINE in the past years, and presents the 10 most influential papers for each year (based on when the paper became available online). This ranking list is automatically constructed based upon citations from both research papers and granted patents, and will be frequently updated to reflect the most recent changes. To find the most influential papers from other conferences/journals, visit Best Paper Digest page. Note: the most influential papers may or may not include the papers that won the best paper awards. (Last updated on: 2022-02-05)

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Treating Cancers Using Nature’s Medicine: Significance and Challenges

Samson mathews samuel.

1 Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar; ude.llenroc.dem-rataq@6102sms

Peter Kubatka

2 Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia; [email protected]

Dietrich Büsselberg

There was a time when plant-derived natural formulations were the cornerstone of ancient therapeutic approaches for treating many illnesses [ 1 ]. With the advent of science-based ‘modern’ medicine, plant-based natural remedies for treating ailments came under intense scrutiny for their lack of scientific basis [ 1 ]. However, researchers kept seeking to identify the scientific basis of herbal remedies, medicinal plants, and functional foods. In recent decades, the emphasis on identifying therapeutic plant-based active principles led to significant advancements in the identification and use of natural compounds to treat various diseases ( Figure 1 ) [ 2 , 3 ]. Much of the current knowledge of medicinal plants and their therapeutic properties derives from traditional Chinese or Indian medicine [ 3 ]. It is notable that an estimated 25–28% of modern medicines used by humanity, including those applied for the treatment of cancers, are directly or indirectly derivatives/compounds obtained from plants or other natural sources [ 3 , 4 ].

Pharmacological effects of natural compounds in various diseases. Naturally derived compounds have been used for their anti-oxidant, anti-diabetic, anti-cancer, anti-microbial, anti-inflammatory, immuno-modulatory, cardio-/vasculo-/hepato-/nephro-, and neuro-protective effects. Created with http://biorender.com/ .

Cancers remain a major cause of death worldwide and significantly contribute to the social and economic burden. There remains an unmet need to develop cancer prevention strategies for those at risk and improve treatment strategies for the benefit of those already affected. Only a minor proportion of cancers are caused by hereditary or genetic predisposition. Cancers often develop over years or even decades, triggered by different processes involving DNA damage, epigenetic modifications, metabolic alterations, chronic inflammation, interactions between aberrant molecular pathways, inhibition of apoptosis, and cellular cross-talk with neighboring tissues. Interestingly, plant-based natural compounds can target one or more of these neoplasticity-triggering mechanisms and thus suppress the initiation, progression, metastatic spread, and relapse of cancers.

The Content of this Special Issue. This Special Issue in Biomolecules , entitled “Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges”, provides a broad and up-to-date overview of the significant aspects encompassing the research and developments in the use of plant-derived natural compounds in the treatment of various cancers.

Eighteen manuscripts are published in this Special Issue, including one feature paper from among eight published original research articles and one feature paper, as well as two editor’s choice articles, from among ten published review articles.

In their featured original article, Woo et al. [ 5 ] identified the ability of honokiol, a traditional Chinese-medicine-based natural biphenolic compound (extracted from Magnolia species), to target and sensitize cancer cells to undergo TRAIL-mediated apoptosis. Honokiol treatment in cancer cells correlated with the degradation and downregulation of anti-apoptotic survivin and c-FLIP. Interestingly, honokiol exposure led to the inhibition of STAMBPL1 (deubiquitinase), which, in turn, facilitated the ubiquitin–proteasome system-linked degradation of survivin and c-FLIP.

Takac et al. [ 6 ] investigated the effect of acridine chalcone 1C (AC1C) in human colorectal cancer cells. They observed that pro-oxidant properties of AC1C support the production of ROS and RNS, promoting mitochondrial dysfunction, DNA damage, and the activation of apoptosis in these cells via the activation of the MAPK-signaling mechanism. Using the anti-oxidant N-acetyl cysteine, the authors reversed the effect of AC1C, which further supported the anti-proliferative/pro-apoptotic effects of AC1C-induced oxidative stress in the colorectal cancer cells.

In most cancers, post-chemotherapy-induced leukopenia (CIL) significantly contributes to the higher mortality rates among patients. In their retrospective pilot study, Varughese et al. [ 7 ] indicated that a diet inclusive of green jackfruit flour, ‘Jackfruit365 (JF365)’, significantly reduced CIL in cancer patients who were also treated with pegfilgrastim. This study should pave the way for further in-depth investigations to identify the active component for this CIL-suppressing effect of JF365.

Abhinand et al. [ 8 ] studied the multiple anti-angiogenic targets of an herbal formulation, triphala churna (THL), prepared from dried fruits from three medicinal plants used in ancient Indian ayurvedic medicine. THL contains over a dozen different phytochemicals, each of which can pharmacologically inhibit tumor progression. However, with their approach of combining in silico (docking) and in vitro techniques, the team identified that punicalagin and chebulagic acid, among other components of THL, were key contributors inhibiting angiogenesis by targeting multiple components of the VEGF/VEGFR2 axis.

Clove is a well-recognized spice used in many cuisines all over the globe. Cloves are utilized to treat an upset stomach and as an expectorant. Clove oil is well known for its anesthetic effect, which helps to quickly relieve a toothache. Clove bud extracts (CBE) were used by Kello et al. [ 9 ] to showcase their ability to induce oxidative stress and DNA damage and activate apoptosis in human breast cancer cells. CBE treatment increased ROS- and RNS-related stress and activated the caspase-dependent apoptotic pathways while significantly modulating these cells’ Akt, p38MAPK, JNK, and ERK ½ pathways.

Isothiocyanates, which are abundant in cruciferous vegetables (Brassicaceae family such as broccoli, brussels sprouts, cabbage, and cauliflower), have been well studied for their chemopreventive chemotherapeutic effects in cancers. Treatment with Benzyl isothiocyanate (BITC), a degradation product of glucosinolates, found in edible plants of the Brassicaceae family, caused cell shrinkage and suppressed cell viability in gastric adenocarcinoma cells [ 10 ]. Han et al. [ 10 ] found that the BITC treatment-induced ROS production, and subsequent mitochondrial dysfunction, led to the mitochondria-mediated cytochrome-c release and caspase-dependent apoptosis. In another study, 6-(methylsulfinyl) hexyl isothiocyanate (6-MITC), a wasabi compound, inhibited the growth and viability of human leukemia cells by the concurrent induction of autophagy and mitotic arrest [ 11 ].

Nineteen different stilbenoids (phenolic compounds found in berries) were investigated by Treml et al. [ 12 ] to study their pro-/anti-oxidant properties in a cellular model of THP-1 macrophage-like cells. Their results show that the different stilbenoids can act as either pro-oxidants or anti-oxidants, and an in-depth study on how these characteristics can be used to combat various cancers is warranted.

Breast cancer remains the leading cause of cancer-related morbidity and mortality worldwide. Three of the review articles have focused on the potential anti-cancer effects of phytochemicals in breast cancers. In their featured review article, Varghese et al. [ 13 ] focused on the mechanism of tumor angiogenesis in light of the altered metabolism of tumor endothelial cells and how miRNAs influence this process in breast cancers. The authors looked through several miRNAs that modulated angiogenesis in breast cancer. They outlined several plant-derived natural compounds (cardamonin, resveratrol, silibinin, curcumin, metformin, genistein, triptolide luteolin, among others) that can alter several miRNA-dependent targets to block tumor angiogenesis and thus repress breast cancer growth and proliferation. In an editor’s choice review article from the same group, Samuel et al. [ 14 ] focused on the widely used anti-diabetic drug metformin as a cancer-preventive and chemotherapeutic agent in treating breast cancer. The article outlines the molecular mechanism of metformin action. It provides an in-depth discussion of the available cellular, pre-clinical, and clinical studies that have tested the anti-tumor potential of metformin as a potential anti-cancer/anti-tumor agent in breast cancer therapy. Abu Samaan et al. [ 15 ] reviewed the clinical effects of paclitaxel (PTX, a taxane compound first isolated from the Pacific yew tree), a commonly used chemotherapeutic drug, and provided mechanistic insights into its anti-cancer effect in different types of breast cancers. While discussing the novel advances in the application of PTX in breast cancers and the use of PTX in neoadjuvant therapy in combination with other anti-cancer drugs, the review also highlights its side effects, the development of resistance to PTX in breast tumors, and possible ways to overcome this treatment-induced resistance to PTX.

In a second editor’s choice article, Samec et al. [ 16 ] discuss the epigenetic post-translational histone modifications as the basis of antineoplastic effects of several phytochemicals in breast, prostate, and colorectal cancers. The authors provide the basis of histone modifications as molecular regulators of chromatin structure. They reviewed the effects of monotherapy and combination therapy using natural compounds on curbing breast, prostate, and colorectal cancers. Along the same theme of epigenetic modifications, Jasek et al. [ 17 ] reviewed the aberrant modifications in the function of DNA methyltransferases (DNMTs) as crucial triggers in the pathogenesis of human cancers. They looked at several pre-clinical and clinical studies that showcase the ability of phytochemicals and plant-based diets to target the epigenetic regulators and modulators of gene transcription and the activity of DNMTs and DNA methylation status in curbing tumor growth and progression.

Gastrointestinal (GI) cancer and its increasing incidence and rapid progression is the theme of Al-Ishaq et al.’s [ 18 ] article. The authors focus on several modifiable and non-modifiable risk factors for the increase in GI cancers and how several bioactive plant-derived secondary metabolites and diets rich in such phytochemicals reduce the incidence (chemopreventive effect) and progression (therapeutic effect) in cancers of the GI tract. They summarize several key molecular mechanisms/pathways (such as the PI3K/Akt, AMPK, mTOR, MAPK, NF- κB, Wnt/β-catenin pathways) that are modulated by natural compounds such as carotenoids, proanthocyanidins, isothiocyanates, and several other plant-metabolites to curb tumor growth and progression.

Brain tumors (high-grade malignant gliomas, including glioblastoma and anaplastic astrocytoma) are among the most devastating and rapidly growing cancers. The chemotherapeutic effect of resveratrol (a polyphenolic component found in berries, nuts, grapes, and red wine) on malignant brain tumors is the focus of the review from Kiskova et al. [ 19 ]. The authors discuss in vitro and in vivo studies that pave the way for advanced clinical research in this area to test resveratrol and its efficacy in treating brain tumors.

Lichens are fascinating symbiotic organisms found in nature and capable of producing different phenolic compounds, including anthraquinones, xanthones, dibenzofurans, depsides, and depsidones. In their review article, Solárová et al. [ 20 ] discuss the molecular mechanisms responsible for the anti-neoplastic potential of several lichen-derived secondary metabolites. While Abotaleb et al. [ 21 ] reviewed the therapeutic potential of different plant-derived phenolic compounds in the treatment of cancer, Satheesh et al. [ 22 ] discuss the possibility that using vitamin C in combination with other conventional anti-cancer treatments can eradicate cancer stem cells (key contributors to therapeutic resistance, metastasis, and relapse).

Are “Natural Substances” the Answer to More Efficient Anti-Cancer Therapy? The articles published in this Special Issue prove that plant-based natural formulations are a vital source of chemopreventive and chemotherapeutic agents. Phytochemicals have a plethora of biological anti-cancer activities and could thus be a rational and practical approach to the effective treatment of cancers. While science and pharmaceutics have made significant advancements in chemically synthesized pharmacological anti-cancer agents and the early diagnosis and identification of cancers, the unfortunate truth is that modern medicine is desperately short of new and targeted therapeutic approaches. It takes years for a new drug to get through research and development and into clinical use, and this is accompanied by high costs [ 3 ]. The once sidelined, natural/plant-based remedies offer ways of relieving this crisis of drug development and harnessing naturally available active compounds to make cancer therapeutics more efficient, as well as more cost-effective and attainable to less privileged patients.

Standard cancer treatment strategies (surgery and radiation) and routinely used chemotherapeutic drugs, in combination with natural bioactive compounds ( Figure 2 ), could prove to be more efficient in treating cancers in terms of (1) a reduction in drug dosage, (2) alleviating side-effects, (3) overcoming drug resistance by re-sensitizing cancers to respond to drugs, (4) targeting cancer stem cells, and (5) curbing metastases and relapses in cancers [ 23 , 24 ].

Benefits of combination therapy (using natural compounds in anti-cancer treatment). The conventional cancer treatments include surgical removal of the tumor, chemotherapy, and radiation therapy, in addition to the standard therapeutic procedures, depending on the type/sub-type of cancer. In a heterogeneous population of cancer patients, while conventional/standard treatment practices benefit some patients, in others, the treatment strategy may have little to no effect. In such a scenario, using a natural compound in combination with the conventional/standard treatment procedures may prove to be beneficial in several ways. Created with http://biorender.com/ .

With the advancements in genomics and understanding regarding the existence of genetic diversity between different patient populations, and even among individual patients, the world of modern medicine is fast embracing the concept of and need for preventive, personalized, precision medicine (3P medicine). In this scenario, when drugs tailored to treat patients on a case-by-case basis become important, turning to ‘natural sources’ of reliable drugs may help to ease the challenges. A serious clinical problem in cytotoxic anti-cancer therapies is the acquired resistance or insensitivity of cancer cells to conventional chemotherapeutics. The current research highlights the potential importance of phytochemicals in increasing chemotherapeutic agents’ sensitivity and/or efficacy against cancer [ 25 ]. Targeting specific molecular pathways by the use of plant nutraceuticals can improve therapeutic outcomes by increasing the sensitivity of cancer cells and reversing their resistance towards the currently applied therapeutic modalities, and thus represents an essential clinical approach to improving the clinical management of cancer. In this regard, testing conventional chemotherapies, in combination with phytopharmaceuticals, on patient-derived cancer cells, using progressive methods, can predict the patient responses and provide outputs for a personalized approach in an individual.

Although this Special Issue focuses on ‘plant-derived natural compounds in cancers’, we acknowledge that ‘natural sources’ for bioactive compounds with medicinal properties are found not just in terrestrial plants but throughout nature, and can help treat various other diseases, as well as cancer [ 26 ]. The marine environment, microbes (bacteria and fungi), slime molds, lichens, and unexpected sources of medicinal remedy, such as the saliva of the Gila monster (the compound found in the saliva, which turned out to be the basis for exenatide, a synthetic anti-diabetic drug), have yielded remarkable therapeutic agents for the treatment of numerous diseases [ 26 ]. Analgesics (painkillers), anti-biotics/anti-microbials, anti-malarials, drugs to treat metabolic and cardiovascular diseases as well as diseases of the nervous and digestive systems, and potential drugs to treat COVID-19, are just few examples of the many therapeutic benefits that humanity has received from from nature [ 27 , 28 , 29 , 30 , 31 ].

Lessons to be Learned and Taught. It is time that differences in opinions regarding the ‘better’ treatment option between practitioners of traditional and modern medicine be set aside, and the different groups work together for the greater good of humanity. On the one hand, practitioners of traditional natural medicine must be willing to share their knowledge. On the other hand, scientists, researchers, and clinicians must support and protect those who practice traditional/natural medicine and be willing to learn from them and their experiences. The knowledge gained from traditional medicine should go hand-in-hand with the pharmaceutical industry’s expertise in drug development [ 3 ]. The lack of international standardization when evaluating the composition, efficacy, safety, and quality of natural medicinal compounds in therapeutics must be overcome [ 3 ]. Coordination and collaboration is necessary between local, regional, national, and international drug regulatory agencies and the pharmaceutical industry to provide clear guidelines regarding the scientific data on the therapeutic effects of compounds derived from natural sources and the regulation/approval processes and manufacturing practices for new drugs [ 3 ].

While there is so much to thank nature for, there is so much more to gain from it. It is likely that we have barely scratched the surface of the medicines that nature has to offer us. Hence, there remains an imminent need to protect our planet from the threats of drastic climate change and unnecessary human interventions that erode and destroy natural resources and their molecular diversity, ultimately depriving humanity of potential sources of natural medicines. Let us play a part in protecting nature and, in turn, let nature protect us!

This work was supported by a National Priorities Research Program grant (NPRP11S-1214-170101; awarded to Professor Dr. Dietrich Büsselberg, June 2019–present) from the Qatar National Research Fund (QNRF, a member of Qatar Foundation). The statements made herein are solely the responsibility of the authors.

Conflicts of Interest

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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• Published: 13 September 2024

Stronger commitment and faster action against antimicrobial resistance

Nature Reviews Microbiology volume  22 ,  pages 589–590 ( 2024 ) Cite this article

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• Antimicrobial resistance
• Antimicrobials

As the United Nations convenes its second High-Level Meeting on antimicrobial resistance, urgent global action is needed. This Focus issue draws attention to pressing challenges of bacterial antimicrobial resistance and underscores the need for fast and coordinated international efforts.

Antimicrobial resistance (AMR) poses a tremendous threat to global health, economies and security. The continued emergence and evolution of antimicrobial-resistant microorganisms puts modern medicine and public health responses at risk, as we will not be able to treat common infections. Treatment of specific diseases will also become challenging, including cancer treatment, transplants and other surgeries, leading to substantial increases in mortality. In 2022, a study assessed the global burden associated with drug-resistant infections and reported that an estimated 4.95 million deaths were associated with bacterial AMR, of which 1.27 million deaths were directly attributable to drug resistance 1 . This global survey revealed that in 2019, drug-resistant infections killed more individuals than HIV/AIDS or malaria. Worryingly, it was estimated that by 2050, AMR could cause up to 10 million deaths 2 , which is comparable with the number of deaths caused by cancer in 2020. As if these staggering numbers were not frightening enough, the study also highlighted inequalities in the AMR crisis, as the highest burdens are carried in the low-resource settings, in countries that have the least means, resources or infrastructure to tackle the problem. The overuse and misuse of antibiotics in many countries contrasts with the lack of access to effective antibiotics in other regions. Effective surveillance and diagnostics are urgently needed, but they are lacking or limited in low-resource regions. The urgent need for the development of new antibiotics or novel treatment strategies is far outpaced by rising AMR, and no clear clinical leads have progressed to shelves yet.

The impact of AMR cannot be overstated, as it threatens food security, economic stability and the achievement of the 2030 Agenda for Sustainable Development adopted by all United Nations member states in 2015. There is an imbalance between the tremendous threat of AMR and effective action taken to date. Similar to climate change, AMR should be made a priority and more political leadership is needed to take effective action. The AMR crisis should be included in policymaking to emphasize the importance of antibiotic stewardship for human, animal and environmental health, and to ensure equitable access to both existing and novel antibiotics. Innovative funding strategies are needed to incentivize research and development of new antimicrobials and diagnostics, as well as to improve access to antimicrobials and vaccines. In addition, emphasis should be placed on infection prevention, hygiene, and access to clean water and sanitation, as these measures will have a great impact on decreasing infection burden.

The second High-Level Meeting on AMR is convened by the United Nations General Assembly (UNGA) and will take place in September 2024. During this meeting, world leaders and experts from various sectors will assemble to set clear new targets and devise practical strategies to combat AMR. The objective of the 2024 UNGA High-Level Meeting on AMR is to adopt a second political declaration that goes beyond the 2016 declaration, with the aim to “accelerate progress in addressing AMR” 3 . Indeed, a policy brief provided ahead of the UNGA High-Level Meeting on AMR by the ReAct group, which is a multidisciplinary team of experts, including public health and policy experts, microbiologists, physicians and veterinarians, states that “Action taken since the last UNGA High-Level meeting in 2016 to address AMR has been too little and too slow” 4 . To mark this important meeting and to highlight the latest developments in the field, Nature Reviews Microbiology has put together this Focus issue on bacterial AMR, featuring Reviews on drug-resistant tuberculosis, ESKAPE pathogens, health care-associated AMR and the evolutionary emergence of bacterial AMR within patients, as well as Comments on the importance of improving access to antibiotics and the challenges faced by low- and middle-income countries in combating AMR.

“The threat that AMR poses to future human health is immense if this crisis is not tackled fast and appropriately at the global level, with unified efforts”

The threat that AMR poses to future human health is immense if this crisis is not tackled fast and appropriately at the global level, with unified efforts. Time is of the essence, and a global, committed action plan involving international and multisectoral collaboration needs to be implemented at a much faster pace to avoid catastrophic outcomes. Public health experts, researchers, clinicians, politicians and the industrial sector have highlighted these points in the ReAct briefing, stressing the urgency of tackling the AMR crisis and calling for accelerated and more effective action and collaboration. The UNGA High-Level Meeting provides the opportunity to secure strong commitments from world leaders and to establish a clear, fast-paced plan for action. Nature Reviews Microbiology urges global leaders to take decisive, immediate steps to address the escalating AMR crisis.

Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 399 , 629–655 (2022).

O’Neill, J. Tackling Drug-Resistant Infections Globally: Final Report and Recommendations (Review on Antimicrobial Resistance, 2016).

Get ready for the 2024 United Nations General Assembly High-Level Meeting in AMR (FAO, UN, WHO & WOAH, 2024).

ReAct’s Briefing for the UN HLM AMR 2024 (ReAct, 2024).

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Stronger commitment and faster action against antimicrobial resistance. Nat Rev Microbiol 22 , 589–590 (2024). https://doi.org/10.1038/s41579-024-01089-z

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