In a groundbreaking advancement at the intersection of bioengineering and electrochemistry, researchers at KAIST have unveiled a pioneering platform that enables the precise, switch-like control of cellular signaling molecules using electrical cues. This innovative bioelectrosynthesis technology represents a significant leap forward in the ability to modulate complex biological systems with unprecedented spatiotemporal specificity, directly addressing longstanding challenges in the controlled generation of gaseous signaling molecules such as nitric oxide (NO) and ammonia (NH₃).
Cellular communication underpins myriad physiological processes regulating the nervous, immune, and vascular systems. Central to these communications are small signaling molecules, among which nitric oxide and ammonia play pivotal roles due to their involvement in processes like neurotransmission, immune responses, and pH regulation. However, their high chemical reactivity and gaseous, unstable nature have historically made it difficult to apply them exogenously with precision, limiting therapeutic and experimental options. The KAIST research team, led by Professor Jimin Park, has now designed a bioelectrical system that resolves these issues by generating these molecules in situ directly within the cellular microenvironment.
The newly developed platform operates by electrochemically converting a single precursor molecule, nitrite (NO₂⁻), into either nitric oxide or ammonia on demand simply by applying an electrical signal. This modular bioelectrosynthesis approach allows for dynamic modulation of the signaling output, enabling precise control over when, where, and how long specific cellular responses occur. Such spatiotemporal control is akin to flipping a molecular switch, providing a powerful tool for future applications in electroceuticals — a cutting-edge field focusing on electrical modulation of biological systems — as well as electrogenetics and personalized cell therapies.
The design of this platform draws inspiration from natural enzymatic processes involved in nitrite reduction. The team engineered catalysts with distinct metal compositions to selectively steer the electrochemical reactions toward either nitric oxide or ammonia production from the same nitrite precursor. By tailoring the catalytic environment, they developed a copper-molybdenum-sulfur complex (Cu₂MoS₄) that favors ammonia generation, contrasted with an iron-incorporated variant (FeCuMoS₄) that shifts selectivity toward nitric oxide. This careful catalyst engineering underpins the platform’s switch-like behavior.
Extensive electrochemical characterization and computational modeling revealed the mechanistic basis for product selectivity. Iron sites within the FeCuMoS₄ catalyst were found to strongly bind nitric oxide intermediate species, stabilizing these toward release as nitric oxide gas. In contrast, the Cu₂MoS₄ catalyst, lacking those iron sites, facilitates further reduction pathways that culminate in ammonia production. This precise tuning of catalytic function not only endorses the platform’s versatility but also highlights the importance of atomic-scale interactions in dictating bioelectrochemical outcomes.
To validate the biological efficacy of their system, the researchers demonstrated its capability to evoke distinct cellular responses through controlled generation of either nitric oxide or ammonia. In human cells, electrochemically produced nitric oxide was shown to activate transient receptor potential vanilloid 1 (TRPV1) channels, which are ion channels responsive to heat and various chemical stimuli and important in pain signaling pathways. Conversely, ammonia production elevated intracellular pH leading to activation of OTOP1 proton channels, which regulate proton flow and are implicated in sensory transduction.
By finely tuning the voltage applied to the catalysts and adjusting the duration of electrical stimulation, the team achieved precise temporal control over the onset and termination of these cellular signaling events. Spatial control was also demonstrated by localizing the production zones, confirming the potential of this system for highly targeted modulation necessary for complex biological interventions. This level of control effectively mimics a binary switch, turning signaling pathways on and off in living cells with high fidelity.
Professor Jimin Park emphasized the transformative potential of their work, stating that the ability to selectively generate biologically relevant signaling molecules using electrical signals opens new avenues in developing next-generation electroceutical therapies. Such therapies could target neurological disorders or metabolic diseases by precisely modifying cellular behavior without the need for invasive pharmaceuticals, reducing side effects and improving patient outcomes.
Moreover, the bioelectrosynthesis platform offers promising prospects for personalized medicine. Because electrical inputs can be precisely adjusted and tailored to an individual’s physiological needs, therapies derived from this technology may soon enable highly customized interventions, optimized not only for disease but also for unique genetic and cellular profiles. The integration of bioelectrochemical systems with cell-based therapies could revolutionize how treatments are delivered and controlled.
The study’s co-first authors, Ph.D. candidates Myeongeun Lee and Jaewoong Lee, alongside Professors Jimin Park and Jihan Kim, have set a strong precedent for interdisciplinary collaboration bridging chemical engineering, materials science, and cellular biology. Their collaborative efforts exemplify how fundamental scientific insights combined with innovative engineering can produce novel solutions to biological challenges.
This research was published in the July 8, 2025, issue of Angewandte Chemie International Edition and is now publicly accessible via DOI: 10.1002/ange.202508192. The findings underscore the expanding role bioelectrochemistry is playing in crafting new modalities for controlling living systems, heralding a future where electrical biointerfaces enable seamless modulation of life’s molecular circuitry.
As the field progresses, further optimization of catalyst design, integration with implantable devices, and expanded demonstrations in vivo will likely extend the therapeutic and research utilities of this platform. The bioelectrosynthesis approach also raises intriguing possibilities for interfacing electronics with biology at unprecedented levels of precision, fostering innovations in synthetic biology, diagnostics, and regenerative medicine.
In summary, KAIST’s bioelectrosynthesis platform marks a transformational shift in cellular modulation technologies. By leveraging electrochemical principles and advanced catalyst engineering, it overcomes previous limitations related to signaling molecule instability and spatial-temporal control. This versatile system stands poised to open new frontiers in both fundamental biological research and the development of innovative, electrically driven medical treatments targeting some of the most complex physiological systems in the human body.
Subject of Research: Bioelectrosynthesis and selective modulation of cellular signaling molecules using electrochemical platforms.
Article Title: Bioelectrosynthesis of Signaling Molecules for Selective Modulation of Cell Signaling
News Publication Date: August 11, 2025
Web References:
DOI Link to article
References:
Lee, M., Lee, J., Kim, Y., Lee, C., Oh, S.Y., Kim, J., Park, J. (2025). Bioelectrosynthesis of Signaling Molecules for Selective Modulation of Cell Signaling. Angewandte Chemie International Edition. DOI: 10.1002/ange.202508192.
Image Credits: KAIST
Keywords: bioelectrosynthesis, nitric oxide, ammonia, cellular signaling, electrochemical catalyst, electroceuticals, spatiotemporal control, TRPV1 channel, OTOP1 proton channel, nitrite reduction, Cu₂MoS₄ catalyst, FeCuMoS₄ catalyst
