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New nanoarchitectonics of RGD peptide developed using quatsomes as robust tool in tissue engineering.

Researchers of three groups of CIBER-BBN at CSIC and IBEC, have created a versatile platform based on hierarchically nanostructured RGD peptide using quatsomes, with proved enhanced cell adhesion. These findings, which arose within the framework of the intramural project of CIBER-BBN “Molecular Biointerfaces for cell guidance” (DynaMo4Vasc), open new possibilities for tissue engineering.

The participation of two NANBIOSIS units were acknowledged in the publication of the research results: the synthesis of RGD derivatives were performed at NANBIOSIS U3 “Synthesis of peptides unit” of CIBER-BBN at IQAC−CSIC.  And the design and characterization of quatsomes were done at U6 of NANBIOSIS “Biomaterial Processing and Nanostructuring Unit” of CIBER-BBN at ICMAB-CSIC.

Tissue Engineering and cell adhesion

Tissue engineering pursues the development of functional and easy biological substitutes that allow restoring damaged organ or tissue or maintaining their normal function. The newer approach is the combination of appropriate cells and growth factors with a scaffold that supports the tissue or organ.

The scaffold is crucial since it must provide the conditions and the environment for the adequate cell regulation (adhesion, migration, proliferation, and differentiation), as well as the adequate delivery of bioactive factors (growth and adhesion), so that cells form the new tissue with its proper structure and function.

Cell adhesion (the interaction of the cells with its surroundings) is an important phenomenon for the development of appropriate scaffolds for tissue engineering, as it can ultimately determine cell fate. Thus, the study of the factors that govern cell adhesion and its optimization is essential.

The tripeptide Arg-Gly-Asp (RGD) is the most common peptide responsible for cell adhesion. Although the studies of its surface density and spacing at nanoscale have already shown a significant influence on cell adhesion, the impact of its hierarchical nanostructure is still unexplored.

Quatsomes

Quatsomes are non-liposomal nanovesicles which have been shown to be very homogeneous and stable in different media and which can be easily tuned with a wide range of chemical functionalities.

The Nanomol Group (from CIBER-BBN and ICMAB-CSIC) has been working during the last years with these nanoparticles showing their suitability for applications in nanomedicine, (as nanocarriers and nanocontainers to encapsulate drugs and protein cargoes, or as fluorescent dyes for therapy and diagnostics). This expertise led the researcher to explore the integration of quatsomes with relevant molecules and their use once anchored to a surface.

RGD Nanoarchitecnonics

Nanoarchitectonics is a novel concept that refers to multicomponent systems organized through the supramolecular union of nanometer structures where the main players are not the individual nanoparticles but their interactions, giving rise to new functionalities.

The team of researchers developed a versatile platform based on quatsomes as an effective nanoscopic building block to achieve hierarchical nanostructures of the RGD peptide which were further anchored to gold substrate. In comparison with substrates featuring a homogeneous distribution of RGD peptides, the resulting hierarchical nanoarchitectonic surfaces dramatically enhanced cell adhesion.

These findings open many possible pathways for the understanding of cell behaviour and improve the performance of clinical applications like implants and tissue engineering.

Article of reference:

Marc Martínez-Miguel, Miquel Castellote-Borrell, Mariana Köber, Adriana R. Kyvik, Judit Tomsen-Melero, Guillem Vargas-Nadal, Jose Muñoz, Daniel Pulido, Edgar Cristóbal-Lecina, Solène Passemard, Miriam Royo, Marta Mas-Torrent, Jaume Veciana, Marina I. Giannotti, Judith Guasch, Nora Ventosa, and Imma Ratera. “Hierarchical Quatsome-RGD Nanoarchitectonic Surfaces for Enhanced Integrin-Mediated Cell Adhesion” ACS Appl. Mater. Interfaces 2022, 14, 42, 48179–48193 Publication Date:October 17, 2022 https://doi.org/10.1021/acsami.2c10497

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Stable nanovesicles for the delivery of microRNA in cancer treatment

  • Nanovesicles, known as quatsomes, have been successfully engineered to encapsulate and deliver microRNAs for the treatment of tumors.
  • These nanovesicles are produced by a simple GMP compliant process, an unavoidable requirement for the clinical use of new drug candidates.
  • The study, published in Small, has been highlighted in the Women in Materials Science issue of Advanced Materials.

“The beauty of these quatsomes nanovesicles is that they can be easily engineered for the delivery of a variety of nucleic acids. Importantly, they are stable at room temperature, which avoids problems associated to cold chain requirements”, says Nora Ventosa, Scientific Director of NANBIOSIS U6.

MicroRNAs (also known as miRNAs) are small RNA molecules that can interfere with the stability of other RNA molecules (specifically, messenger RNA). They have many potential therapeutic uses due to the central role they play in major diseases. However, these molecules are still infrequently used in patients due to their instability in the bloodstream and their poor ability to reach specific tissues. A potential strategy to improve the clinical delivery of miRNAs in the body is to encapsulate them in tiny carriers that compensate its current shortcomings, without side effects and offering other complementary functions.

To this end, researchers have developed and designed especially for this application nanostructures, known as quatsomes, composed by two closed lipid layers. In a new publication in Small, which is highlighted in the “Women in Materials Science” Issue of Advanced Materials, researchers present a newly engineered formulation of quatsomes that have a controlled structure, composition and pH sensitiveness. 

The study is the result of an interdisciplinary team of researchers from the Institute of Materials Science of Barcelona, ICMAB-CSIC, the Vall d’Hebron Research Institute (VHIR)-UAB,  the Institute for Bioengineering of Catalonia (IBEC), the Barcelona Institute of Science and Technology (BIST),  the CIBER network on Bioengineering, Biomaterails and Nanomedicine (CIBER-BBN), the company Nanomol Technologies SL, the Technion-Israel Institute of Technology and the Institute for Complex Molecular Systems (ICMS).

“In this study we have collaborated with hospitals, research networks and companies. The successful results obtained illustrate the importance of collaboration across fields and beyond the academic system” says Ventosa.

These new quatsomes can be coupled with the miRNA and injected intravenously into the body to be delivered in neuroblastoma primary tumors or in frequent sites of metastasis, such as the liver or lung, with a higher success and stability than if the miRNA were injected by itself. Once delivered, the miRNA has an effect on the cell proliferation and survival-related gens in the tumors, decreasing the tumor’s growth rate.

Many properties make quatsomes a good fit for these applications: they are less than 150 nm in size and are stable in a liquid solution for more than 6 months; they also have tunable pH sensitiveness, which means that different pH levels around can trigger different responses.

Quatsome production and their physicochemical characterization has been performed by the ICTS “NANBIOSIS,” more specifically in the Biomaterial Processing and Nanostructuring Unit (U6), Unit of the CIBER in Bioengineering, Biomaterials & Nanomedicne (CIBER-BBN) located at the Institute of Materials Science of Barcelona (ICMAB-CSIC) and led by Nora Ventosa

The production of these nanovesicles has been optimized with their final application in mind and to make sure they can be used in clinics. Through a green and scalable one-step process, named DELOS, researchers have designed a procedure that is fully compliant with Good Manufacturing Practice (GMP) guidelines stablished by the European Union. “It is time to translate our scientific findings for the benefit of patients” says Ariadna Boloix, VHIR researcher.

The development of miRNA delivery systems containing an active targeting for neuroblastoma is performed under the frame of a CIBER-BBN valorization project “Targeted Quatsome nanocarriers for the delivery of microRNA for neuroblastoma therapy” (TAG-SMARTLY), coordinated by the Nanomol group in collaboration with the Multivalent Systems for Nanomedicine (MS4N) group of the CIBER-BBN at IQAC-CSIC and the Synthesis of Peptides Unit of Nanbiosis (U3).

In this publication, the functionality of quatsomes in delivering miRNAs is demonstrated with a specific extracranial solid tumor common in pediatric cases of cancer known as neuroblastoma, which is responsible for roughly 15 % of all pediatric cancer deaths and lacks therapies for high-risk patients. The results show that quatsomes protect the miRNA from degradation and increase its presence on liver, lung and xenografted neuroblastoma tumors, amongst other tissues.

Reference article:

Engineering pH-Sensitive Stable Nanovesicles for Delivery of MicroRNA Therapeutics Ariadna Boloix, Natalia Feiner-Gracia, Mariana Köber, Javier Repetto, Rosa Pascarella, Aroa Soriano, Marc Masanas, Nathaly Segovia, Guillem Vargas-Nadal, Josep Merlo-Mas, Dganit Danino, Inbal Abutbul-Ionita, Laia Foradada, Josep Roma, Alba Córdoba, Santi Sala, Josep Sánchez de Toledo, Soledad Gallego, Jaume Veciana, Lorenzo Albertazzi, Miguel F. Segura*, Nora Ventosa* Small, 18, 3, 2022 DOI: 10.1002/smll.202101959

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New fluorescent nanovesicles for intracellular biomarker detection

A new work by researchers from the CIBER-BBN at the Barcelona Institute of Materials Science ICMAB-CSIC, together with a team from the University of Rome Tor Vergata, presents new nanovesicles capable of crossing biological barriers such as cell membranes, maintaining their sensory capacity, making them attractive probes for intracellular biomarker detection.

“The development of probes capable of detecting the biological environment and signaling the presence of a specific target molecule is a challenge with relevance in a variety of biomedical applications, from drug administration to diagnostic tools” says Mariana Köber, one of those responsible of the investigation together with Nora Ventosa and Alessandro Porchetta from the University of Rome Tor Vergata.

In this work, which has been published in Advanced Functional Materials, the design of functionalized fluorescent nanovesicles with biomimetic DNA capable of translating their binding with a target molecule into an optical output is presented, through a change in the transfer of resonance energy. Förster (FRET) and fluorescent emission. These Quatsomes (QS) nanovesicles are an emerging class of highly stable small unilamellar vesicles ≈50–100 nm in diameter, formed by the self-assembly of ionic surfactants and sterols in aqueous media. Their high stability, also in body fluids, unilaminarity and particle-to-particle homogeneity make them an attractive soft material for detection applications. “QS nanovesicles are loaded with fluorescent waves based on amphiphilic nucleic acids to produce programmable FRET active nanovesicles that function as highly sensitive signal transducers,” she explains.

The CIBER-BBN researchers have participated in the characterization of the photophysical properties of these nanovesicles and the highly selective detection of clinically relevant microRNAs with sensitivity in the nanomolar range has been demonstrated. This production of nanovesicles and their physicochemical characterization has been carried out thanks to the services of ICTS NANBIOSIS, through its unit 6 of Biomaterials Processing and Nanostructuring at the ICMAB-CSIC.

According to the authors, the proposed strategy could easily be adapted to the detection of different biomarkers: “we hope to achieve a bioimaging platform for the detection of a wide range of nucleic acids and other clinically relevant molecules in body fluids or directly in cells, thanks to the ability of Quatsomes for intracellular delivery. “

  • Figure: Schematic representation of the DNA-grafted QS nanovesicles. Adv Funct Materials, Volume: 31, Issue: 46, First published: 11 August 2021, DOI: (10.1002 / adfm.202103511)

Article of reference

Marianna Rossetti, Lorenzo Stella, Judit Morlà-Folch, Sara Bobone, Ariadna Boloix, Lorena Baranda, Danila Moscone, Mònica Roldán, Jaume Veciana, Miguel F. Segura, Mariana Köber… Engineering DNA-Grafted Quatsomes as Stable Nucleic Acid-Responsive Fluorescent Nanovesicles . https://doi.org/10.1002/adfm.202103511

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