Centro Interdipartimentale di Biotecnologie Molecolari "Guido Tarone"
Sonia Visentin PI
Research activity
Whatever we do in life, it is not possible to exist and function without the world and the things it offers. This is true also for our body: lungs need oxygen and muscles need energy to move. In other words, resources need to get from the outside to the inside. Hence, our body cannot be a closed system and parts of our “inside” are unavoidably in touch with parts of the “outside”. Surprisingly, the very first interface between our body tissues and the overwhelming numbers and types of external stimuli is very often a misunderstood and disqualified actor. Despite its fundamental role, this gatekeeper was named, in our opinion, by one of the most unpleasant, disturbing and underestimated names of biology: mucus.
Our research is centred on the remarkable and yet not fully understood properties of mucus. Employing a highly interdisciplinary approach, we consider mucus not merely as a passive element of human mucosal tissues, but rather as a truly active agent that, through its unique compositional, chemical, mechanical, and biological characteristics, performs essential functions crucial for maintaining our state of health. For these reasons, our primary focus is on the main and key type of proteins forming mucus: the mucins.
Mucins are a family of high molecular weight, heavily glycosylated proteins that confer the protective and lubrication properties of mucus in various tissues and fluids throughout the body, including the respiratory, gastrointestinal, and reproductive tracts.
Several diseases are associated with alterations in mucins production, secretion, or function. For example, it is well-known that mucins are overproduced in the lungs of cystic fibrosis (CF) patients, leading to impaired mucins clearance and increased susceptibility to respiratory infections. With our interdisciplinary approach among chemistry, material science and industry, we developed Bac3Gel, a new and robust Mucins-based technological tool to challenge CF infections (Figure 1). In the case of Bac3Gel, we used mucins as components of an in vitro model exhibiting the key characteristics of the mucus environment, where we observed that the low permeability limit the amount of drug that encounters bacteria, thus affecting its efficacy.
Since the evaluation of efficacy and bioavailability of potential therapeutic molecules depends heavily on permeability assessments, it is an essential step to include mucins in available permeability assay, thus maximising the probability of clinical success. For this reason, we constantly optimise and adapt our mucins-based technology to be integrated within standard and newly-developed tools for rapid-permeability profiling. With our collaborations in industry, we provided insights into the permeability mechanisms of an heterogeneous dataset of drugs in commercial products such as Permeapad, unveiling the physicochemical properties ruling the permeation flux.
In our fundings, mucins and mucus showed in vitro their pivotal role as the primary active filter of our body, with the capability of governing the diffusion of drugs from “outside” to the “inside” (Figure 2).
Despite the remarkable technological advancements and our understanding of human diseases, the successful translation of these advances into therapeutic solutions remains a significant challenge. We aimed at revolutionising the current drug delivery strategies by drawing inspiration from nature itself and harnessing the potential of our body's primary defence mechanism, mucins, as carriers for therapeutic agents.
The implementation of our innovative approach culminated in the development of an entirely new category of nanocarriers: NanoMug (Figure 3). The NanoMug nanocarriers represent a new breakthrough in nanotechnology, as they are made of the distinctive components of mucus, the mucins, conferring remarkable glycosylated bioinspired-branches to the nanocarriers and providing mucoadhesive properties in a unique and stand-alone system. These features enable a high affinity of mucosomes for a wide range of molecules, as well as natural compatibility with both prokaryotic and eukaryotic cells. This makes our approach a suitable nanosystem for tailored drug delivery, but also lays the groundwork for exploring diverse applications simultaneously, including pioneering fields such as gene therapy and cutting-edge diagnostics.
Figure 3. Taking inspiration by native mucins in mucus (A), we developed a easy, controllable and single-step process to produce a new category of nanocarries, NanoMug, with intrinsic affinity for a wide range of molecules as well as biological entities, such as bacteria (B)
Embracing the advances provided by Bac3Gel as a bioinspired environment and NanoMug as a new category of nanocarriers, our natural future research perspective relies on applying our technologies in the frontiers of pharmaceutical sciences, each one considered as a stand-alone tool and in combination. We plan to expand the formulations of Bac3Gel to model both healthy and pathological environments, including cultures of healthy and pathological strains of bacteria or microbiota populations. We also aim at using NanoMugs to craft cutting-edge high-throughput screening tools, as well as to advance the delivery of drugs for cancer treatment and to implement new strategies of immunomodulation.
By exploiting the synergy between Bac3Gel and NanoMug, we pursue to stand at the threshold where science and innovation hold the key to unlock mysteries of biology, in the reimaging of drug delivery and pharmaceutical science.
2020 Project title: Nanoparticelle per combattere la resistenza batterica, Progetti di Ricerca di Ateneo PoC Instrument - Compagnia di San Paolo 2019/20212019.2260
2021 Project title Mucus4COVID: un prototipo di modello in vitro per determinare il ruolo del muco polmonare nell'infezione di Sars-Cov2, la sua trasmissione e lo sviluppo di terapie efficaci per bloccare la (Mucus4Covid), progressione della malattia FISR 2020 Covid
2022 Project title: Smart NIR dye-based wound dressings to fight bacteria Grant for Internationalization - GFI - Programmazione Triennale 21-23
2023 Project title: New generation of substrates to harness the full power of microorganisms, Bac3Gel LDA, EIC accelerator 2023
2023 Project title: Epithelial Exchange Surfaces – From organizing principles to novel culture models of the gatekeepers of the body (SurfEx) HORIZON-TMA-MSCA-DN
2023 Project title: Multitasking mucosomes bioinspired from mucin immunomodulatory and antimicrobial activity: the turning point of the host-pathogen interaction? (MITIGATE ), TRAPEZIO - Linea 1 - Paving the way to research excellence and talent attraction
2023 Project title: Multitasking mucosomes: empowering the immune response of the host while treatment respiratory pathologies (MUMMI), PRIN 2022
2023 Project title: Nature-inspired prophylactic lubricants against HIV-1 and HSV-2 (NatProLub), EIC Pathfinder 2023
1.Peneda Pacheco, D., Bertoglio, F., Butnarasu, C., Suarez Vargas, N., Guagliano, G., Ziccarelli, A.,
Briatico-Vangosa, F., Ruzzi, V., Buzzaccaro, S., Piazza, R., van Uden, S., Crotti, E., Visentin, S.,
Visai, L., Petrini, P. Heterogeneity Governs 3D-Cultures of Clinically Relevant Microbial Communities (2023) Advanced Functional Materials DOI: 10.1002/adfm.202306116
2. Butnarasu, C., Pontremoli, C., Moran Plata, M.J., Barbero, N., Visentin, S.
Squaraine Dyes as Fluorescent Turn-on Probes for Mucins: A Step Toward Selectivity
(2023) Photochemistry and Photobiology, 99 (2), pp. 562-569.
DOI: 10.1111/php.13722
3. Butnarasu, C., Garbero, O.V., Petrini, P., Visai, L., Visentin, S. Permeability Assessment of a High-Throughput Mucosal Platform (2023) Pharmaceutics, 15 (2), art. no. 380
DOI: 10.3390/pharmaceutics15020380
4. Butnarasu, C., Petrini, P., Bracotti, F., Visai, L., Guagliano, G., Fiorio Pla, A., Sansone, E., Petrillo, S.,Visentin, S. Mucosomes: Intrinsically Mucoadhesive Glycosylated Mucin Nanoparticles as Multi-Drug Delivery Platform (2022) Advanced Healthcare Materials, 11 (15), art. no. 2200340,
DOI: 10.1002/adhm.202200340
5. Kretschmer, M., Ceña-Diez, R., Butnarasu, C., Silveira, V., Dobryden, I., Visentin, S., Berglund, P.,
Sönnerborg, A., Lieleg, O., Crouzier, T., Yan, H. Synthetic Mucin Gels with Self-Healing Properties Augment Lubricity and Inhibit HIV-1 and HSV-2 Transmission (2022) Advanced Science, 9 (32), art. no.2203898
DOI: 10.1002/advs.202203898
6. Sardelli, L., Vangosa, F.B., Merli, M., Ziccarelli, A., Visentin, S., Visai, L., Petrini, P.
Bioinspired in vitro intestinal mucus model for 3D-dynamic culture of bacteria
(2022) Biomaterials Advances, 139, art. no. 213022.
DOI: 10.1016/j.bioadv.2022.213022
6. Ghigo, A., Murabito, A., Sala, V., Pisano, A.R., Bertolini, S., Gianotti, A., Caci, E., Montresor, A.,
Premchandar, A., Pirozzi, F., Ren, K., Sala, A.D., Mergiotti, M., Richter, W., de Poel, E., Matthey, M.,
Caldrer, S., Cardone, R.A., Civiletti, F., Costamagna, A., Quinney, N.L., Butnarasu, C., Visentin, S.,
Ruggiero, M.R., Baroni, S., Crich, S.G., Ramel, D., Laffargue, M., Tocchetti, C.G., Levi, R., Conti, M.,
Lu, X.-Y., Melotti, P., Sorio, C., De Rose, V., Facchinetti, F., Fanelli, V., Wenzel, D., Fleischmann,
B.K., Mall, M.A., Beekman, J., Laudanna, C., Gentzsch, M., Lukacs, G.L., Pedemonte, N., Hirsch, E.
A PI3Kγ mimetic peptide triggers CFTR gating, bronchodilation, and reduced inflammation in
obstructive airway diseases (2022) Science Translational Medicine, 14 (638), art. no. abl6328.
DOI: 10.1126/scitranslmed.abl6328
7. Butnarasu, C., Caron, G., Pacheco, D.P., Petrini, P., Visentin, S. Cystic Fibrosis Mucus Model to Design More Efficient Drug Therapies (2022) Molecular Pharmaceutics, 19 (2), pp. 520-531.
DOI: 10.1021/acs.molpharmaceut.1c00644
8. Guillaume, O., Butnarasu, C., Visentin, S., Reimhult, E. Interplay between biofilm microenvironment and pathogenicity of Pseudomonas aeruginosa in cystic fibrosis lung chronic infection (2022) Biofilm, 4, art. no. 100089.
DOI: 10.1016/j.bioflm.2022.100089
9. Peneda Pacheco, D., Suárez Vargas, N., Visentin, S., Petrini, P. From tissue engineering to engineering tissues: The role and application of: The vitro models (2021) Biomaterials Science, 9 (1),
DOI: 10.1039/d0bm01097a
10. Butnarasu, C., Barbero, N., Barolo, C., Visentin, S. Squaraine dyes as fluorescent turn-on sensors for the detection of porcine gastric mucin: A spectroscopic and kinetic study
(2020) Journal of Photochemistry and Photobiology B: Biology, 205, art. no. 111838.
DOI: 10.1016/j.jphotobiol.2020.111838
