Within the inner sanctum of cellular biology, the impermeability of cellular membranes to many therapeutic molecules stands as a monumental barrier to effective treatment. Proteins and peptides, though potent in their therapeutic potential, are often rendered ineffectual because they cannot penetrate the phospholipid bilayers that guard the cell’s interior. Traditional drug delivery systems have long grappled with this challenge, employing mechanisms grounded in classical principles of molecular transport. The CARAMEL project dares to rethink these foundational assumptions by proposing a radical strategy based on covalent chaotropic membrane transport, a concept that proposes the use of covalent interactions combined with chaotropic agents to transiently disrupt membrane integrity, thereby facilitating the ingress of otherwise impermeable biomolecules.

The interdisciplinary team spearheading CARAMEL comprises four principal investigators, each a luminary in their respective fields. Dr. Werner Nau from Constructor University in Germany brings extensive expertise in supramolecular chemistry and molecular transport phenomena. Dr. Paola Luciani of the University of Bern, Switzerland, is renowned for her work in membrane biophysics and chemical biology. Dr. Oliver Hantschel from Philipps University of Marburg, Germany, contributes cutting-edge insights into oncogenic signaling pathways and therapeutic targeting. Anchoring this collaboration is Dr. Javier Montenegro from the Center for Research in Biological Chemistry and Molecular Materials (CiQUS), University of Santiago de Compostela, Spain, who serves as the corresponding principal investigator. Together, they form a synergistic team equipped to unravel the complexities of intracellular delivery through innovative chemical design and biological exploration.

Central to CARAMEL’s innovation is the abandonment of traditional, often limiting presuppositions regarding molecular transporters. Classical methods typically employ molecular carriers or liposomal encapsulation that rely on established pathways for endocytosis or membrane fusion. In contrast, the covalent chaotropic approach envisages designing transporters that transiently and reversibly bind to membrane components, inducing local disorganization at the molecular level. Such induced disorder—rooted in chaotropic effects that destabilize the structured water and lipid environment—enables these transporters to ferry large, hydrophilic biomolecules across the otherwise impermeable lipid bilayer. This disruptive method, if successful, could unlock a previously inaccessible avenue for targeted delivery within cells, expanding therapeutic possibilities immensely.

Javier Montenegro, reflecting on the significance of the ERC Synergy Grant, emphasized the novelty and transformative potential of their concept. “Our project represents a paradigm shift in understanding membrane transport mechanisms,” he stated. “By harnessing covalent interactions in combination with chaotropic disruption, we are exploring a fundamentally new transport mode that may pave the way for a new class of biotherapeutic delivery agents. This could ultimately change how we treat intracellular diseases, including a broad spectrum of cancers.” This bold vision reflects the project’s ambition to transcend incremental improvements and instead catalyze a conceptual overhaul in drug delivery science.

The potential impact of the CARAMEL project extends far beyond the confines of chemical innovation. Effective intracellular delivery of therapeutic proteins and peptides has historically been a crucible for drug development, often limiting the clinical applicability of these agents despite their therapeutic promise. By systematically investigating the fundamental mechanics of covalent chaotropic membrane transport, the team aims to establish a robust proof-of-concept that could be rapidly translated into clinical applications. This approach offers hope not only for more efficacious cancer therapies but also for treatments spanning metabolic disorders, infectious diseases, and genetic conditions where intracellular targeting is crucial.

A distinctive strength underpinning this collaborative effort is the ERC Synergy Grant’s emphasis on integrative, collaborative research approaches. Unlike individual grants, the Synergy Grant fosters convergence from multiple scientific disciplines, enabling this team to tackle an extraordinarily complex problem from complementary perspectives. The union of chemical biology, supramolecular chemistry, membrane biophysics, and therapeutic oncology embedded within CARAMEL exemplifies how scientific frontiers can be advanced when diverse expertise is harnessed in concert. This integration also accelerates the iterative process of hypothesis generation, experimental validation, and therapeutic design that is vital for tackling the intricacies of intracellular delivery systems.

Exploring the molecular intricacies of covalent chaotropic transport necessitates advanced chemical synthesis combined with high-resolution biophysical characterization. The team anticipates employing groundbreaking techniques such as single-molecule fluorescence spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, and advanced electron microscopy to observe membrane interactions in real-time at a molecular scale. Complemented by computational modeling and molecular dynamics simulations, these tools will illuminate how transporter molecules interact transiently yet specifically with lipid domains, perturbing the membrane environment just enough to allow passage of therapeutic cargo without compromising cellular viability.

Moreover, CARAMEL’s research is poised to address the long-standing challenge of specificity in drug delivery. Covalent chaotropic transporters can be chemically engineered to recognize specific cell types or pathological states by tuning their reactive groups and membrane affinity profiles. This specificity is particularly critical in cancer therapeutics, where targeted delivery minimizes off-target effects and maximizes drug efficacy within tumor cells. By refining the molecular architecture of these transporters, the project aims to achieve selective cytoplasmic entry, thereby enhancing therapeutic indices and patient outcomes.

The project’s timeline, spanning up to six years, allows for comprehensive stages of research and development—from initial theoretical modeling and chemical synthesis, through in vitro validation of transport efficacy, to in vivo testing in preclinical models of disease. This methodical progression ensures that each phase builds on robust scientific data, reducing translational risks and accelerating pathways towards clinical trial readiness. The sustained funding of nearly €10 million underscores the ERC’s commitment to fostering long-term, high-impact research endeavors that may redefine therapeutic landscapes.

In conclusion, the CARAMEL project exemplifies how visionary scientific ideas, supported by strategic interdisciplinary collaboration and forward-thinking funding mechanisms, can embark on the path to redefine fundamental paradigms in medicine. By confronting the molecular barriers that have thwarted intracellular delivery for decades, this team seeks not only to unlock new frontiers in cell biology and biochemistry but also to usher in a new era of biotherapeutic interventions that are more effective, selective, and transformative. The scientific community and patients alike await the outcomes of this trailblazing research with keen anticipation.

Keywords: Drug delivery, covalent chaotropic membrane transport, biotherapeutic delivery, intracellular transport, peptides, proteins, membrane permeability, membrane transporters, chemical biology, cancer therapy, molecular transport, European Research Council, Synergy Grant

The blood-nerve barrier serves as a protective shield for the nervous system, structured as a selective barrier that regulates the passage of substances between blood circulation and nerve cells. This barrier is essential not only for maintaining the homeostasis of nerve environments but also for providing nutrients and shielding nerve cells from potentially harmful toxins. Understanding its intricate workings is vital, especially as damage to this barrier is associated with numerous painful conditions. These include nerve damage related to diabetes, cancer treatments, and various inflammatory disorders affecting the nervous system.

Teesalu’s research group has garnered support from leading research teams across Europe, creating a powerful consortium aimed at scrutinizing the blood-nerve barrier. Their collaborative efforts will generate a comprehensive molecular and spatial map, shedding light on the interactions between nerve cells and blood vessels. The peripheral nervous system, which encompasses all nerves outside the brain and spinal cord, will be the focal point of their innovative research.

The collaboration is set to last for six years, promoting the exchange of ideas among four prominent research groups. Led by Teesalu, the consortium includes experts like Professor Ellie Tzima from the University of Oxford, who will investigate the effects of mechanical stress on the barrier’s biological functions. Simultaneously, Dario Bonanomi’s team at Italy’s San Raffaele Hospital will explore neurobiology and nerve regeneration mechanisms. In parallel, Isabelle Brunet’s team at the Collège de France will bridge the realms of neuroscience and vascular biology, enhancing the scope of this multidisciplinary approach.

One of the project’s primary objectives is to identify specific molecules known as homing peptides. These peptides can target and guide therapeutic agents directly to the appropriate cells by leveraging the unique molecular markers present in blood vessels—akin to a postal system. So far, Teesalu’s previous work has primarily concentrated on solid tumors and brain delivery systems. However, the focus on the peripheral nervous system offers a fresh perspective on drug delivery methods.

As the researchers embark on this transformative journey, they are poised to identify barriers and improve the binding properties of therapeutic molecules to enhance the effectiveness of treatments directed at nerve pain. Chronic nerve pain is a condition affecting a significant proportion of the global population, making this research pivotal in addressing a pressing health concern. While immediate clinical applications are not expected, the discoveries from this project may pave the way for future breakthroughs in pain management.

Teesalu expresses optimism about the project’s implications for understanding chronic nerve pain, emphasizing that unveiling the mechanisms of the blood-nerve barrier is essential to manipulating its properties for therapeutic advantages. Furthermore, he underscores the importance of future investigations into how this barrier impacts nerve cell repair and healing processes—a topic that remains largely unexplored.

This ERC Synergy Grant is not Teesalu’s first achievement in securing such funding; he is notably the only Estonian researcher to have received ERC support three times. These previous accolades include an ERC Starting Grant in 2012 and a Proof of Concept Grant in 2018. His continued success reflects not only his innovative research capabilities but also the critical relevance of his work in advancing nanomedicine and its potential applications.

The project’s financial backing is impressive, with a total budget of 10 million euros, allowing the consortium to pursue comprehensive research over the designated six-year period. Teesalu’s research group has been allocated 2.5 million euros to further their investigations into this crucial area of study. This substantial funding emphasizes the value placed on this research endeavor within the broader scientific community and its potential to yield valuable insights into chronic pain management.

As the global prevalence of chronic pain continues to rise, addressing the underlying mechanisms of the blood-nerve barrier may significantly improve our understanding of pain pathophysiology. Insights gained from this research could lead to novel therapeutic options for patients suffering from diverse pain conditions, ultimately transforming the paradigm of pain treatment.

In conclusion, the collaborative effort spearheaded by Teesalu and his European partners marks a pivotal moment in neurobiology and the field of nanomedicine. By unlocking the blood-nerve barrier’s secrets, they aim to introduce innovative approaches to drug delivery that could revolutionize treatment options for millions of individuals living with chronic pain. This endeavor promises to lay the groundwork for enhanced therapies and improved patient outcomes in the future.

Subject of Research: Drug delivery across the blood-nerve barrier

Article Title: Unlocking the Secrets of the Blood-Nerve Barrier: A Revolutionary Approach to Pain Management

News Publication Date: October 2023

Web References: [N/A]

References: [N/A]

Image Credits: Photo by Andres Tennus

Keywords

blood-nerve barrier, chronic pain, Tambet Teesalu, ERC Synergy Grant, drug delivery, nanomedicine, peripheral nervous system, homing peptides, nerve regeneration, neuroscience, inflammation, therapeutic approaches

The core thematic focus of this meeting was “Integration,” a principle that runs deeply through SELINA’s expansive framework comprising eleven distinct yet interconnected Work Packages. By fostering enhanced coherence among these groups, the workshop aimed to optimize the diverse expertise and outputs cultivated thus far, setting the trajectory for an aligned approach in the project’s forthcoming phases. Over the span of four intensive days, participants engaged in thorough evaluations of scientific progress, synergizing their findings to bolster the translational capacity of SELINA’s research into tangible, policy-relevant tools.

Among the most significant developments announced was the official launch of a dedicated Community of Practice (CoP) portal on the SELINA website. This online platform represents a major leap forward in knowledge sharing and stakeholder engagement, enabling continuous exchange among researchers, decision-makers, and practitioners dispersed across Europe. The CoP framework is designed as a dynamic vehicle to augment collaborative learning, foster innovation in ecosystem service assessments, and streamline dissemination of best practices, thereby reinforcing the network’s responsiveness to emergent environmental and socio-political needs.

Attention was also given to the Compendium of Guidance (CoG), a fundamental SELINA tool that distills complex interdisciplinary methodologies into accessible, operational guidance. The workshop’s interactive sessions facilitated an in-depth review of the CoG’s evolving content, emphasizing its role in standardizing protocols for integrated biodiversity and ecosystem service evaluations. This standardization serves as a cornerstone for enhancing the comparability and interoperability of ecological data across varying European contexts, ultimately supporting evidence-based decision-making at multiple governance levels.

Crucially, the 5th Workshop spotlighted the emerging Early Career Research Network (ECRN), a platform fostering cross-generational dialogue and capacity building among newer researchers within the environmental sciences. By providing targeted mentoring and fostering collaborative projects, the ECRN acts as an incubator for innovative approaches and fresh perspectives essential for navigating the complexities of simultaneous biodiversity conservation and ecosystem management challenges. This focus on nurturing early-career experts ensures continuity in expertise and sustains the vitality of SELINA’s scientific community.

The collaborative spirit permeated the workshop’s numerous working group sessions, where participants engaged hands-on to share insights, troubleshoot methodological limitations, and co-develop integrative frameworks. These exercises proved instrumental in breaking down disciplinary silos, facilitating a deeper understanding of how ecological indicators can be harmonized with societal values and policy imperatives. The multidisciplinary dialogue fostered at the event signals a paradigm shift towards genuinely integrative science, which SELINA strives to exemplify.

Throughout the meeting, feedback from international experts was solicited during the Advisory Board sessions, further enriching the discourse with external perspectives. These critiques and endorsements serve not only to validate ongoing efforts but also to identify strategic gaps and emerging priorities, ensuring that SELINA’s research trajectory remains robust and adaptive. The infusion of external expertise is a testament to the project’s commitment to transparency, scientific rigor, and responsiveness to the broader research and policy communities.

Benjamin Burkhard, Project Coordinator and a professor at Leibniz University Hannover, reflected on the intense transdisciplinary interactions, remarking on the inspiring environment of São Miguel Island. The rich biodiversity and unique ecosystem services of the Azores provided a living laboratory, motivating participants to renew their commitment to SELINA’s mission. This blend of place-based inspiration and scientific endeavor encapsulates the ethos of SELINA—linking ecological complexity with practical sustainability targets.

This workshop builds on the foundations laid in previous SELINA events across Europe, including Sofia, Madrid, Leiden, and Trondheim. Each iteration has progressively deepened the collaborative fabric of the consortium, refining methodologies and expanding stakeholder engagement. The baton now passes to the University of Trento in Italy, host of the forthcoming 6th workshop scheduled for October 2025, where these accumulated insights will be further advanced.

As SELINA approaches the midpoint of its project timeline, it steadfastly pursues its ambitious goal of producing interdisciplinary knowledge that is not only scientifically profound but also immediately relevant for decision-making. The integration of ecological, social, and economic data streams enables the generation of nuanced, actionable insights to guide biodiversity conservation and ecosystem management, addressing pressing challenges like habitat fragmentation, climate change impacts, and sustainable resource use.

At its core, SELINA exemplifies the modern paradigm of environmental research where collaboration across sectors, disciplinary boundaries, and geographic regions is vital. By institutionalizing tools like the Communities of Practice and the Compendium of Guidance, the project sets a new standard for how scientific consortia can operate effectively at the science-policy nexus. This model may serve as a blueprint for other large-scale environmental initiatives seeking to reconcile complex biodiversity data with policy frameworks.

Engagement and dissemination remain paramount as SELINA’s layers of research unfold. Leveraging a multi-platform strategy that includes its website and active presence on social media channels such as LinkedIn, Bluesky, and YouTube, the project ensures broad accessibility and real-time communication with diverse stakeholders. This openness not only democratizes knowledge but also catalyzes wider adoption and scaling of SELINA-developed approaches across the European continent.

Looking ahead, the SELINA Consortium remains optimistic yet vigilant about the challenges inherent in such ambitious endeavors. The evolving environmental landscape demands innovative, integrative science that can anticipate and respond to dynamic socio-ecological conditions. SELINA’s ongoing commitment to co-producing interdisciplinary, policy-relevant knowledge, grounded in active stakeholder involvement, positions it as a critical contributor to Europe’s biodiversity and ecosystem service agendas in the decades to come.

Subject of Research: Integrated biodiversity and ecosystem service assessments for European environmental policy and management.

Article Title: SELINA Consortium Advances Integration and Collaboration at the 5th Thematic Workshop in the Azores

News Publication Date: May 2025

Web References:

• SELINA Project Website
• SELINA LinkedIn
• SELINA Bluesky
• SELINA YouTube Channel

Image Credits: Pensoft Publishers

Keywords: Science communication, Science policy, Scientific organizations