First Multi-Responsive Foldamer-Based Gel Offers New Approach to Controlled Drug Delivery

University of Birmingham scientists have industrialized the first multi-responsive, foldamer-driven gel, which utilizes palladium-linked synthetic molecules that switch between solid and liquid states via light, heat, or acid.

A research team at the University of Birmingham has advanced the first multi-responsive gel constructed from foldamers – synthetic molecules that fold into defined shapes, allowing switching between gel- and liquid-based states in response to UV light, heat, and acid.

Scientists at the University of Birmingham have industrialized a responsive material that could provide a novel strategy for controlled drug delivery because of its ability to switch between gel- and liquid-based states in response to various chemical and physical triggers.

The material, described in the Journal of the American Chemical Society, is the first multi-responsive gel reported to be built from foldamers, synthetic molecules that fold into definite shapes and assemble, disassemble, and reassemble on demand.

The scientists say the platform could finally help inform the advancement of drug delivery systems allows of therapeutic molecules in response to particular conditions.

Multiple Triggers for Drug Release

The material can be switched from a solid-like gel to a flowing, liquid-like state using ultraviolet (UV) light. Heating reverses the process and reforms the gel, while acid offers a separate mechanism for breaking down the molecular network.

This integration of responses could be relevant to pharmaceutical applications where control over when and where a therapeutic molecule is released is significant.

Dr Maria Chiara Arno, Associate Professor in Polymeric Biomaterials in the School of Chemistry at the University of Birmingham, said: “Supramolecular materials are assembled using reversible interactions rather than permanent chemical bonds. That allows us to create materials that are robust under normal conditions but can be reorganised or dismantled when we apply the right signal.”

This organization converted the material from an organic solvent-driven gel into a hydrogel containing water, deprived of disrupting its underlying structure. Hydrogels are widely used in biotechnology and medicine because they hold massive amounts of water while maintaining mechanical integrity.

“This represents a significant advance in building materials that behave more like biological systems by responding intelligently to their surroundings - for example, releasing drugs only when exposed to a specific trigger, such as changes in acidity within diseased tissue."

Molecular Design Controls Material Behaviour

The gel consists of helical foldamer molecules connected by palladium ions, which act as four-way molecular connectors to make a prolonged network that traps liquid.

UV light shifts the shape of light-sensitive components in the foldamers. Although the transformation arises at the molecular level, it is propagated throughout the network, causing the gel to lose its solid-like structure.

Heating enables the network to reform, while acid acts through various mechanisms by disrupting the interactions among the foldamers and palladium ions.

Dr Sarah Pike, Associate Professor of Organic Chemistry at the University of Birmingham, said: “A very small change in molecular shape translates into a visible change in the whole material – demonstrating how carefully designed molecular components can give us control over the behaviour of a bulk gel.

“The research is at a fundamental stage, but the ability to programme more than one response into the same material could ultimately inform the design of smart sensors, switchable catalysts, and materials that capture and release selected molecules on demand.”

For drug discovery and advancement, the capability to engineer materials that respond to their environment could be specifically relevant to controlled release and delivery technologies. Additionally, the researchers stress that the work remains at a significant stage.

Revealing the Structure

Understanding the molecular behavior of the material was essential for the study. The team employed dynamic nuclear polarisation-enhanced solid-state NMR (DNP NMR) to analyze the gel’s structure. This method significantly shortened experiment times; what would take about seven years with standard NMR was accomplished in only 12 hours using DNP NMR. 

Dr Dominik Kubicki, Associate Professor in Materials Characterisation at the University of Birmingham, said: “Seeing a material change is only half the story. If we want to design better responsive gels, we need to know precisely how their molecular building blocks are connected. DNP NMR gave us that atomic-level picture in a material that is otherwise exceptionally difficult to study – allowing us to solve a major challenge in gel science.”

The researchers foresee future uses in targeted drug delivery, controlled release of therapeutic agents, biomedical materials, as well as smart sensing and catalysis.

According to Towards Healthcare, the drug delivery devices market is projected to grow significantly, with estimates indicating the market size will increase from USD 500.23 billion in 2026 to approximately USD 986.7 billion by 2035, expanding at a CAGR of 7.84% from 2026 to 2035. Recent advancements in drug delivery devices provide significant advantages as compared to conventional drug delivery systems, including enhanced performance, automation, precision, and effectiveness. They are made of nanomaterials or miniaturized tools with multifunctional components that are biocompatible, biodegradable, and have high viscoelasticity with an increased mixing half-life. Drug delivery systems are technological systems that formulate and store drug molecules into suitable forms, such as tablets or solutions for administration.

A recent report by Towards Healthcare highlights that the Drug Delivery Devices Market is growing, as advanced drug delivery devices in recent years have seen a significant rise in demand because they provide significant advantages related to their applications. From reducing healthcare expenses to offering timely reminders related to the medication’s prescribed dosage, integrated drug delivery devices ensure that the patient gets the perfect medical care treatment. Advanced drug delivery tools are basically smart electronic health devices that store critical patient therapeutic information like time, dosage, and site of administration for self-administration by the patient.