Bioorganic and supramolecular carbohydrate chemistry
The scientific interests of our Research Group revolve around the development and implementation of synthetic tools that enable well-defined molecular systems to perform specific functions in biological environments. In this context, we explore the interactions of these synthetic molecules with biologically relevant targets (nucleic acids and proteins) and how they can interfere with the (bio)chemical processes that occur in living organisms. The knowledge generated by our research allows us to drive the development of cutting-edge molecular tools for various biotechnological and biomedical applications.
Main research areas
1.- Carbohydrates for Health and Wellbeing
Leaders: José Manuel García Fernández and Juan Manuel Benito Hernández
Research activity in this area falls into three different categories:
- Glycoproteins for the treatment of metabolic diseases, with a special focus on lysosomal storage disorders, neurodegenerative diseases associated with ageing (e.g. Parkinson’s or Alzheimer’s) and immune system disorders (inflammation, cancer, autoimmune diseases such as asthma). To this end, we design carbohydrate mimetics and glycoconjugates (glycomimetics) with effector, inhibitor, agonist/antagonist or regulatory properties on the enzymes and biological receptors associated with the target pathologies.
- Glycotransporters of therapeutic substances, from low molecular weight drugs and analogues to biomacromolecules, with a special focus on nucleic acids. This axis takes advantage of the inherent structural and supramolecular properties of cyclodextrins and focuses on the development of precise molecular adaptation strategies to transform them into molecular nanoparticles with the capacity for self-assembly or co-assembly in the presence of the therapeutic payload. Addressing this challenge from a molecular perspective allows us to implement rational approaches to adapt and programme delivery capabilities.
- Glycobiotics with prebiotic and nutraceutical activity and their application in the prevention and treatment of inflammatory bowel diseases. Along these lines, we develop technologies to transform carbohydrates present in conventional diets into families of oligosaccharides rich in prebiotics with nutraceutical properties, aimed at the prevention and treatment of inflammatory bowel diseases (e.g., Crohn’s disease and ulcerative colitis).
Current Challenges and Milestones
In recent years, the team’s activity has focused on a novel concept for the development of delivery systems for nucleic acids or artificial/synthetic viruses based on molecularly well-defined carbohydrates. The challenge lies in designing systems based on strictly monodisperse species that are compatible with single-component formulations as alternatives to lipid nanoparticles (LNPs), currently the standard for the delivery of non-viral nucleic acids, popularized by mRNA-based vaccines against the SARS-CoV-2 pandemic. The objective is to overcome the limitations and drawbacks inherent in these technologies, in relation to (i) the complexity inherent in optimizing multicomponent LNP formulations, (ii) limited loading capacity, (iii) immunological adversities, or even (iv) intellectual property issues.
Our results in this field demonstrate the strategic soundness of adapting diverse delivery capabilities (efficiency, targeting, payload capacity, etc.) while maintaining biocompatibility and scalability. Furthermore, the molecular and monodisperse nature of these artificial viruses allows for the rational modulation of their functional properties by leveraging structure-activity relationship (SAR) screening. One such screening is being conducted in collaboration with BioNTech (Mainz, Germany), which has led to the development of an innovative mRNA delivery technology and a broad portfolio of intellectual property.
2.- Supramolecular Chemistry of Peptides, Glycopeptides, and Glycomacrocycles
Leaders: Alejandro Méndez Ardoy
This research area focuses on self-assembly and molecular recognition using synthetic glycoconjugates and specifically designed peptide conjugates, with functional applications such as molecular detection and transport. We also explore their potential in systems chemistry, for example, through the incorporation of energy dissipation mechanisms.
3.- Organic and Supramolecular Chemistry of Macrocycles
Leaders: Alejandro Díaz Moscoso
The objective of this research line is to advance the understanding and control of interactions between derivatives of cyclic macromolecules (cyclodextrins, porphyrins, phthalocyanines, etc.) and biomolecules (nucleic acids and proteins) through research in organic and supramolecular chemistry. Advances in this area allow us to develop new molecular tools for specific applications.
- Molecular tools for light-controlled biotechnological applications: We design multifunctional systems by combining macrocyclic molecules with complementary properties and characteristics (e.g., inclusion and photochemical properties). This allows us to externally control their performance in different processes, facilitating the study and development of new applications.
- Encapsulation and release of active (bio)molecules: We study the assembly and disruption processes of well-defined supramolecular complexes capable of encapsulating other molecules within them. The knowledge acquired allows us to design multimolecular transport systems that improve the stability and efficiency of active (bio)molecules (e.g. enzymes, catalysts, etc.), potentially allowing us to control their activity.
José Manuel García Fernández
CSIC Research Professor
Sergio Adorna Sánchez
PhD Student
Verónica Raposo Mantis
Youth Guarantee Technique
- G. Varan, N. Demirtürk, J. M. Benito, M. Malanga, S. Can Öztürk, G. Esendağlı, E. Bilensoy, CD44-Targeted cyclodextrin-hyaluronic acid nanoparticles carrying gemcitabine and paclitaxel to pancreatic cancer, Eur. J. Pharm. Sci. 2026, 221, 107527. DOI: 10.1016/j.ejps.2026.107527 IF: 4.7 (JCR 2024) Clasificación: Q1, 54/352 (Pharmacology & Pharmacy) Public repository (DIGITAL.CSIC): http://hdl.handle.net/10261/429099
- Azobenzene-bridged ionizable amphiphilic Janus glycosides for light-controlled, single-component and organ-modulable pDNA delivery. Z. Wang, G. Rivero-Barbarroja, J. M. Benito, S. Maisonneuve, I. Vélaz, I. Juárez-Gonzálvez, M. J. Garrido, C. Tros de Ilarduya, C. Ortiz Mellet, J. Xie, J. M. García Fernández. Commun. Chem. 2026, 9, 118. DOI: 10.1038/s42004-026-01920-z.
- Neutral sp2-iminosugars exploiting non-glycone interactions for selective acid α- and β-glucosidase activity modulation: Pharmacological chaperones for Gaucher and Pompe diseases. M. I. García-Moreno, K. Kawakami, E. Nanba, J. M. García Fernández, K. Higaki, C. Ortiz Mellet, Eur. J. Med. Chem. 2026, 304, 118500. DOI: 10.1016/j.ejmech.2025.118500. Scopus link: https://www.scopus.com/pages/publications/105024881742
- Enhanced RNA-targeting CRISPR-Cas technology in zebrafish. I. Moreno-Sánchez, L. Hernández-Huertas, D. Nahón-Cano, P.M. Martínez-García, A.J. Treichel, C. Gómez-Marin, L. Tomás-Gallardo, G. da Silva Pescador, G. Kushawah, R. Egidy, A. Perera, A. Díaz-Moscoso, A. Cano-Ruiz, J.A. Walker II, M.J. Muñoz, K. Holden, J. Galcerán, M.A. Nieto, A.A. Bazzini, M.A. Moreno-Mateos. Nat. Commun., 2025, 16, 2591. DOI: 10.1038/s41467-025-57792-9
- β-Cyclodextrin-based geometrically frustrated amphiphiles as one-component, cell-specific and organ-specific nucleic acid delivery systems. G. Rivero-Barbarroja, J. López-Fernández, I. Juárez-Gonzálvez, C. Fernández-Clavero, C. Di Giorgio, I. Vélaz, M. J. Garrido, J. M. Benito, C. Ortiz Mellet, F. Mendicuti, C. Tros de Ilarduya, J. M. García Fernández. Carbohydr. Polym. 2025, 347, 122776 (WoK Polymer Science; D1 3/95) DOI: 10.1016/j.carbpol.2024.122776. Scopus link:https://www.scopus.com/pages/publications/85204882316
- α-GalCer sp2-iminoglycolipid analogs as CD1d-dependent iNKT modulators: Evaluation of their immunotherapeutic potential in murine models of asthma and autoimmune hepatitis A. Chuan-Ying Lai, M. González-Cuesta, C.-H. Ho, P.-Y. Chi, K.-C. Wu, G. Rocha, J. C. Muñoz-García, J. Angulo, J. M. García Fernández, Y.-J. Chang, C. Ortiz Mellet. Eur. J. Med. Chem. 2025, 282, 117060 (WoK Chemistry, Medicinal; Q1, 8/72) . DOI: 10.1016/j.ejmech.2024.117060. Scopus link:https://www.scopus.com/pages/publications/85209245774
- Trehalose-polyamine/DNA nanocomplexes: impact of vector architecture on cell and organ transfection selectivity. F. Ortega-Caballero, M. L. Santana-Armas, C. Tros de Ilarduya, C. Di Giorgio, R. Tripier, N. Le Bris, C. Ollier, C. Ortiz Mellet, J. M. García Fernández, J. L. Jiménez Blanco, A. Méndez-Ardoy. J. Mater. Chem. B 2024, 12, 3445-3452 (WoK Material Science, Biomaterials; Q1, 11/53). DOI: 10.1039/D3TB02889E. Scopus link: https://www.scopus.com/pages/publications/85188300182
- Serine-/cysteine-based sp2‑iminoglycolipids as novel TLR4 agonists: Evaluation of their adjuvancy and immunotherapeutic properties in a murine model of asthma. M. González-Cuesta, A. C.-Y. Lai, P.-Y. Chi, I-L. Hsu, N.-T. Liu, K.-C. Wu, J. M. García Fernández, Y.-J. Chang, C. Ortiz Mellet. J. Med. Chem. 2023, 66, 4768-4783 (WoK Medicinal Chemistry; D1, 3/63). DOI:10.1021/acs.jmedchem.2c01948. Scopus link: https://www.scopus.com/pages/publications/85151350325
- Reversible light-induced dimerization of secondary face azobenzene-functionalized β-cyclodextrin derivatives. G. Rivero-Barbarroja, C. Fernández-Clavero, C. García-Iriepa, G. Marcelo, M. C. Padilla-Pérez, T. Neva, J. M. Benito, S. Maisonneuve, C. Ortiz Mellet, J. Xie, J. M. García Fernández, F. Mendicuti. J. Org. Chem. 2023, 88, 8674-8689 (WoK Organic Chemistry; Q1, 12/56). DOI:10.1021/acs.joc.3c00564. Scopus link:https://www.scopus.com/pages/publications/85164376568
- Potent and Selective Cell-Active Iminosugar Inhibitors of Human α-N-Acetylgalactosaminidase (α-NAGAL). R. A. Ashmus, Y. Wang, M. González-Cuesta, D. T. King, B. Tiet, X. Chen, Y. Zhu, B. Kirk, J. M. García Fernandez, C. Ortiz Mellet, R. Britton, D. J. Vocadlo. Chem. Eur. J. 2023, 29, e202300982 (WoK Multidisciplinary Chemistry; Q2, 66/178). DOI:10.1002/chem.202300982. Scopus link: http://scopus.com/pages/publications/85164102650
- Mannobioside biomimetics that trigger DC-SIGN binding selectivity. I. Herrera-González, M. Thépaut, E. M. Sánchez-Fernández, A. di Maio, C. Vivès, J. Rojo, J. M. García Fernández, F. Fieschi, P. M. Nieto, C. Ortiz Mellet. Chem. Commun. 2022, 58, 12086-12089 (WoK Multidisciplinar Chemistry; Q2, 53/179). DOI: 10.1039/d2cc04478a. Scopus link:https://www.scopus.com/pages/publications/85140830318
- Enhanced gene delivery triggered by dual pH/redox responsive host-guest dimerization of cyclooligosaccharide star polycations. A. I. Carbajo-Gordillo, J. López-Fernández, J. M. Benito, J. L. Jiménez Blanco, M. L. Santana-Armas, G. Marcelo, C. Di Giorgio, C. Przybylski, C. Ortiz Mellet, C. Tros de Ilarduya, F. Mendicuti, J. M. García Fernández. Macrmol. Rapid Commun. 2022, 43, 2200145 (WoK Polymer Science; Q1, 15/90). DOI:10.1002/marc.202200145. Scopus link: https://www.scopus.com/pages/publications/85128502519
- Bicyclic picomolar OGA inhibitors enable chemoproteomic mapping of its endogenous post-translational modifications. M. González-Cuesta, P. Sidhu, R. A. Ashmus, A. Males, C. Proceviat, Z. Madden, J. C. Rogalski, J. A. Busmann, L. J. Foster, J. M. García Fernández, G. J. Davies, C. Ortiz Mellet, D. J. Vocadlo. J. Am. Chem. Soc. 2022, 144, 832-844 (WoK Multidisciplinar Chemistry; D1, 16/179). DOI:10.1021/jacs.1c10504. Scopus link: https://www.scopus.com/pages/publications/85122666291
- Complementary Syntheses Giving Access to a Full Suite of Differentially Substituted Phthalocyanine‐Porphyrin Hybrids. F. Alkorbi, A. Díaz‐Moscoso, J. Gretton, I. Chambrier, G.J. Tizzard, S.J. Coles, D.L. Hughes, A.N. Cammidge. Angw. Chem. Int. Ed., 2021, 60, 7632 – 7636. I.F.: 16.823. 15/179 – CHEMISTRY, MULTIDISCIPLINARY – Q1. DOI: 10.1002/anie.202016596HIGHLIGHTED by Nachrichten aus der Chemie, 2022, 70, 42-69 – as “Trendbericht Organische Chemie 2022” (Trends in Organinc Chesmitry 2022) (DOI: 10.1002/nadc.20224122453).
- Trifaceted Mickey Mouse Amphiphiles for Programmable Self-Assembly, DNA Complexation and Organ-Selective Gene Delivery. A. I. Carbajo-Gordillo, M. González-Cuesta, J. L. Jiménez Blanco, J. M. Benito, M. L. Santana, T. Carmona, C. Di Giorgio, C. Przybylski, C. Ortiz Mellet, C. Tros de Ilarduya, F. Mendicuti, J. M. García Fernández. Chem. Eur. J. 2021, 27, 9429-9438 (WoK Multidisciplinar Chemistry; Q2, 52/179). DOI:10.1002/chem.202100832. Scopus link:https://www.scopus.com/pages/publications/85106473902
Diseño y estudio de sistemas de transporte molecular para desarrollar terapias génicas fotodinámicas eficientes frente a tumores sólidos (FOTOGEN)
Project OTR15969 funded by:
Scientific Research Grants Project
Validity: Ene 2026/Ene 2027
IP: Alejandro Díaz Moscoso
New prototype for the efficient and safe delivery of nucleic acids: Molecular glycoviromers (GLYCOVIR).
Project DGP_PIDI_2024_00465 funded by:
Applied Research and Experimental Development Project
Validity: Abr/2026 a Abr/2029
IP: J. M. García Fernández / M. I. García Moreno
Customized Immunomodulatory Glycolipids for Vaccine and non-Vaccine Therapies
Project BILAT23023 funded by:
CSIC – Academia Sinica (Taiwan)
Reference: BILAT23023 (21.990,24 €)
Validity: Ene/2024 a Dic/2025
IP J. M. García Fernández
Bicyclos – Breaking down barriers to foster new Cyclodextrin-based applications for healthcare by implementing sustainable design principles
Project 101130235 funded by:
MSCA-Staff Exchange program
Reference: 101130235 (179.400 €)
Validity: Desde Sep/2023 a Ago/2027
IP J. M. García Fernández
Website: https://www.bicyclos.eu/
Charge-reversible molecular glycomers: stimuli responsiveness, immunoregulation, and targeting
Project PID2024-157753OB-C21 funded by:
MICIU, Proyectos generación de conocimiento
Reference: PID2024-157753OB-C21 (247.500 €)
Validity: Sep/2025 a Ago/2028
IP J. M. García Fernández; co-IP J. M. Benito
Development of a sustainable purification strategy as an alternative to chromatography RSC Sustainable Laboratories Grant
Project L24-9306838105 funded by:
Reference: L24-9306838105
Validity: Abr/2025 a Mar/2027
IP A. Díaz Moscoso; co-IP A. Méndez Ardoy
Sistemas Moleculares Basados en Carbohidratos y Péptidos para el Transporte de Ácidos Nucleicos
Project 2024ICT084 funded by:
Extraordinary Grants for the Incorporation of Tenured Scientists of the CSIC 2024.
Reference: 2024ICT084
Validity: Jun/2024 a May/2026
IP A. Díaz Moscoso
Transportadores de ADN/ARN de nueva generación: cápsides moleculares basadas en carbohidratos
Project PID2021-124247OB-C21 funded by:
IP:José Manuel García Fernández y Juan Manuel Benito Hernández
Validity: 01/09/2022 – 31/08/2025
Oligosaccharide compounds and complexes.
J. Moreno Herrero, H. Haas, S. Erbar, J. M. García Fernández, C. Ortiz Mellet, J. M. Benito, J. López Fernández, J. L. Jiménez Blanco.
PCT/EP2022/079340.
21/10/2022. BioNTech, CSIC, Univ. Sevilla. Licensed to BioNTech.
Web: https://patentscope.wipo.int/search/en/WO2023067121
Oligosaccharide complexes and uses.
J. Moreno Herrero, H. Haas, S. Erbar, J. M. García Fernández, J. M. Benito, J. López Fernández.
PCT/EP2022/079342.
21/10/2022. BioNTech, CSIC. Licensed to BioNTech.
Web: https://patentscope.wipo.int/search/en/WO2023067123
Disulfide oligosaccharide compounds and complexes.
Moreno Herrero, H. Haas, S. Erbar, J. M. García Fernández, J. M. Benito, J. López Fernández, P. Sánchez Mellado.
PCT/EP2022/079343.
21/10/2022. BioNTech, CSIC. Licensed to BioNTech.
Web: https://patentscope.wipo.int/search/en/WO2023067124
Oligosaccharide compounds and complexes.
Moreno Herrero, H. Haas, S. Erbar, J. M. García Fernández, J. M. Benito, J. López Fernández, P. Sánchez Mellado.
PCT/EP2022/079346.
21/10/2022. BioNTech, CSIC. Licensed to BioNTech.
Web: https://patentscope.wipo.int/search/en/WO2023067126
Oligosaccharide complexes and uses.
Moreno Herrero, H. Haas, S. Erbar, T. B. Stahl, J. M. García Fernández, J. M. Benito, J. López Fernández, C. Ortiz Mellet, N. de la Cruz Ruiz, M. González Cuesta, E. J. J. Ambuludi, I. Vlatkovic.
PCT/EP2022/079345.
21/10/2022. BioNTech, Univ. Sevilla, CSIC. Licensed to BioNTech.
Web: https://patentscope.wipo.int/search/en/WO2023067125
Glycolipid compositions.
Metelkina, M. Gangluff, N. Agrawal, S. Schille, J. Moreno Herrero, A. Kuriakose Thomas, J. M. García Fernández, J. M. Benito, N. de la Cruz Ruiz, M. J. Puerto Madorran.
PCT/EP2023/085641.
13/12/2023. BioNTech SE, CSIC. Licensed to BioNTech.
Web: https://patentscope.wipo.int/search/en/WO2025124711
Multiantennary glycolipid mimetics.
M. García Fernández, C. Ortiz Mellet, M. González Cuesta, I. Herrera González, Y.-J. Chang, A. C.-Y. Lai.
PCT/EP2022/079553.
24/10/2022. CSIC, Univ Sevilla, Academia Sinica.
5-Aminohexahydro-6,7,8-trihydroxy-3H-oxazolo[3,4-a]pyridin-3-one derivatives as TLR4 modulators for the treatment of immune diseases.
M. García Fernández, C. Ortiz Mellet, M. González Cuesta, E. M. Sánchez Fernández, Y.-J. Chang, A. C.-Y. Lai.
PCT/EP2022/079912.
26/10/2022. CSIC, Univ Sevilla, Academia Sinica.
Immunomodulatory thiourea and urea carbohydrate compounds and uses thereof.
M. García Fernández, A. Parejas Barranco, C. Ortiz Mellet, M. González Cuesta, K. Maenaka, P. A. Gillén Poza, A. Furukawa.
EP24382585.8.
31/05/2024.
CSIC, Univ Sevilla, Hokkaido Univ., Kanazawa Univ.