How Cold Plasma's Reactive Species Are Revolutionizing Medicine
In the heart of a tiny electrical storm, scientists have found a new key to fighting superbugs, healing wounds, and even combating cancer.
Imagine a device that looks like a small pen, emitting a faint, violet beam of light. This beam, a form of cold atmospheric plasma, can kill antibiotic-resistant bacteria without damaging healthy human skin. It can decontaminate a packaged food product without cooking it, and even kickstart the healing process in chronic wounds that have refused to close for years. The secret to these remarkable abilities lies not in the electrical current itself, but in a rich, dynamic cocktail of reactive oxygen and nitrogen species (RONS) that the plasma generates in liquids—the very medium of life. This is the story of the chemistry and biochemistry of cold physical plasma-derived reactive species, a frontier where physics meets biology to create tomorrow's medicine.
To understand the revolution, we must first understand the state of matter. We are taught that matter exists as solids, liquids, and gases. Add enough energy to a gas, however, and you create the fourth state of matter: plasma. Think of the sun, lightning, or the glow of a neon sign.
For decades, using plasma in medicine was unthinkable because it was thousands of degrees hot. The breakthrough came with the development of cold atmospheric plasma (CAP). By creating plasma under specific conditions, scientists can now generate it at room temperature, safe enough to touch living tissue. This cold plasma is a unique mix of free electrons, ions, neutral atoms, and photons. But its most crucial components for medicine are the RONS it produces 4 8 .
When this "liquid lightning" interacts with water or biological fluids, it deposits a complex blend of these reactive species, turning the liquid itself into a potent, yet controllable, therapeutic agent. This is the core of a burgeoning field known as plasma medicine 1 .
Fixed shape and volume
Fixed volume, adapts shape
No fixed shape or volume
Ionized gas with unique properties
The power of cold plasma is harnessed through the reactive species it generates. These are divided into two main families, each with distinct roles:
This group includes hydrogen peroxide (H₂O₂), the hydroxyl radical (·OH), superoxide (O₂·⁻), and ozone (O₃). They are powerful oxidizing agents, capable of damaging microbial cells and triggering specific signaling pathways in human cells 1 .
Oxidizing Agents Antimicrobial Cell SignalingThis group features nitric oxide (NO), nitrogen dioxide (·NO₂), and peroxynitrite (ONOO⁻). RNS are particularly important in wound healing, as they mimic signaling molecules our bodies already use to regulate blood flow and immune responses 7 .
Cell Signaling Wound Healing Immune RegulationSome of these species are short-lived, like the hydroxyl radical, which acts in a flash of biochemical activity. Others, like hydrogen peroxide and nitrite, are long-lived, allowing them to diffuse and exert effects over longer periods and distances 4 .
| Reactive Species | Type | Lifespan | Primary Functions & Importance |
|---|---|---|---|
| Hydroxyl Radical (·OH) | ROS | Short-lived | Extremely reactive; causes significant damage to microbial cell components 2 . |
| Hydrogen Peroxide (H₂O₂) | ROS | Long-lived | A stable oxidant; can penetrate cells and induce oxidative stress and signaling . |
| Nitric Oxide (NO) | RNS | Short-lived | A key biological signaling molecule; involved in vasodilation and immune regulation 7 . |
| Peroxynitrite (ONOO⁻) | RNS | Short-lived | Powerful oxidant formed from NO and superoxide; can nitrate proteins, altering their function 7 . |
| Superoxide (O₂·⁻) | ROS | Short-lived | A precursor to other ROS; contributes to oxidative stress . |
The biological impact of plasma's reactive species is a tale of two sides. On one hand, they can be ruthlessly efficient destroyers; on the other, delicate cellular messengers.
The fight against antibiotic-resistant bacteria is one of the most pressing challenges in modern medicine. Cold plasma offers a multi-targeted strategy that microbes struggle to defend against. The antimicrobial attack happens on several fronts 4 :
Key Advantage: Because this attack is physical and multi-pronged, bacteria do not easily develop resistance to it, making plasma a promising "antibiotic-free" antimicrobial modality 4 .
Perhaps even more fascinating is plasma's ability to selectively promote healing. Lower, controlled doses of RONS can mimic the body's own redox signaling processes. In wound healing, for instance, plasma-derived RNS like nitric oxide can stimulate blood flow, cell migration, and tissue regeneration 7 8 .
This dual nature—destroying pathogens while stimulating our own cells—is what makes cold plasma such a unique and powerful tool.
The therapeutic window of plasma treatment is key: at higher concentrations, RONS cause destructive oxidative stress, while at lower concentrations, they activate protective and regenerative cellular pathways.
To truly appreciate how this science works, let's look at a recent 2025 study that combined cold plasma with gold nanoparticles to target melanoma, a deadly form of skin cancer 2 .
The researchers designed a sophisticated experiment to test the synergy between two powerful agents:
Human melanoma cells and healthy fibroblast cells were cultured in lab plates.
The cells were incubated with gold nanoparticles (GNPs). These tiny particles are stable and known to be taken up more readily by cancer cells than healthy ones.
A helium-generated cold plasma jet was applied to the cells for varying durations (30, 60, and 90 seconds). Some cells received only GNPs, some only plasma, and some received the combination.
The findings were striking. The combination of cold plasma and gold nanoparticles was significantly more effective at inducing apoptosis in melanoma cells than either treatment alone. Crucially, healthy cells remained largely unaffected, demonstrating the selectivity of this approach 2 .
Even more remarkable was the discovery that cold plasma enhanced the uptake of gold nanoparticles in cancer cells but not in healthy ones. This suggests plasma can act as a "gate opener," selectively helping therapeutic agents penetrate their target. The experiment also confirmed that plasma treatment led to a significant production of highly reactive hydroxyl radicals, which are primary drivers of cancer cell damage 2 .
| Treatment Group | Cancer Cell Apoptosis | Effect on Healthy Cells | GNP Uptake in Cancer Cells | Hydroxyl Radical Production |
|---|---|---|---|---|
| Gold Nanoparticles (GNP) Only | Moderate | Minimal | Baseline | None |
| Cold Plasma Only | Significant | Minimal | Not Applicable | Significant |
| GNP + Cold Plasma | Most Significant | Minimal | Enhanced | Most Significant |
The following table details some of the essential reagents and tools used by scientists in this field to unravel the effects of cold plasma.
| Reagent / Tool | Function in Research | Specific Example |
|---|---|---|
| Terephthalic Acid (TA) | A chemical dosimeter; it reacts with hydroxyl radicals (·OH) to form a fluorescent compound, allowing for indirect measurement of this short-lived radical 2 . | Used to confirm and quantify ·OH generation during plasma treatment. |
| DMPO Spin Trap | Used in Electron Paramagnetic Resonance (EPR) spectroscopy to "trap" and detect short-lived free radicals like ·OH and superoxide, which would otherwise be invisible . | Directly identified and quantified ·OH radicals in plasma-activated media (PAM). |
| Annexin V / Propidium Iodide | Fluorescent dyes used in flow cytometry to distinguish between live, early apoptotic, late apoptotic, and necrotic cells 2 . | Demonstrated that plasma+GNP treatment selectively pushes cancer cells into apoptosis. |
| Gold Nanoparticles (GNP) | Used as a therapeutic agent and a tracer; their high electron density and stability make them ideal for studying cellular uptake and synergistic effects 2 . | ICP-OES measured increased GNP uptake in cancer cells post-plasma treatment. |
| kINPen Plasma Jet | A well-characterized, certified medical-grade atmospheric plasma jet. Its chemistry and effects are extensively studied, making it a benchmark in the field 7 . | Used in mechanistic studies to link specific RNS like peroxynitrite to biological outcomes like wound healing. |
The applications of this technology are rapidly expanding. The journey of cold plasma from a physics curiosity to a biomedical tool is a powerful reminder that some of the most profound solutions can come from the most unexpected places.
Cold plasma devices are already CE-marked in Europe for wound healing and are being trialed for cancer therapy and dentistry 8 .
"In-package" cold plasma treatment can decontaminate sealed products without heat, preserving freshness and nutrition 5 .
Used to enhance the extraction of bioactive compounds from plants for use in medicines and nutraceuticals 6 .
The subtle, violet glow of the plasma jet represents not just an electrical discharge, but a beacon of hope for tackling some of medicine's most persistent challenges, all by harnessing the power of reactive species born from "liquid lightning."