An innovative drug delivery system has demonstrated a 40-fold reduction in antibiotic concentration needed to destroy bacterial biofilms.
Researchers at the University of Oxford have engineered a promising new weapon in the fight against antibiotic-resistant infections. Their innovative drug delivery system uses ultrasound-activated nanoparticles to physically break through and destroy bacterial biofilms, addressing a significant challenge in treating chronic diseases.
Bacterial biofilms, present in up to 80% of chronic infections, form when bacteria secrete a protective slimy substance, creating a matrix around themselves. This matrix shields bacteria from human immune cells and antimicrobial drugs, making them up to 1,000 times more resistant to treatment than free-floating bacteria.
“Biofilms are very difficult to remove without mechanically breaking them up, which is not straightforward to do inside the body,” explains Professor Eleanor Stride, Principal Investigator of the project and Professor of Biomaterials at the University of Oxford.
The protective matrix makes conventional antibiotic treatments largely ineffective and often requires invasive surgical intervention or prolonged high-dose antibiotic regimens, which can further contribute to antibiotic resistance.
To tackle this problem, engineers from Oxford’s Department of Engineering Science and the Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences (NDORMS) developed antibiotic-loaded nanoparticles that can be precisely activated at infection sites.
The nanoparticles contain antibiotics and are designed to vaporize rapidly when exposed to ultrasound. This vaporization creates a dual effect: physically disrupting the biofilm matrix while releasing antibiotics directly at the infection site.
A key advantage of this approach is that ultrasound can be precisely focused deep inside the body, allowing for non-invasive targeting of infections in areas that might otherwise require surgical intervention.
The system works by loading antibiotics into specially engineered nanoscale particles. When these particles are activated by focused ultrasound, they quickly vaporize, creating a mechanical disruption that breaks apart the biofilm’s protective matrix.
This disruption does two crucial things: it physically tears open the biofilm, allowing the immune system better access to the bacteria, and it releases the antibiotic cargo precisely where it’s needed, achieving higher local concentrations with lower overall doses.
For infections embedded deep in tissues, the ability to focus ultrasound energy at specific locations means treatments can be targeted without damaging surrounding healthy tissue.
The research team tested their nanoparticles against ten clinical bacterial strains, including E. coli and methicillin-resistant Staphylococcus aureus (MRSA), delivering four antibiotics.
The results were striking. Combining nanoparticles and ultrasound reduced the antibiotic concentration by more than 10-fold compared to conventional treatment in bacteria that did not form biofilms.
The results were even more impressive for biofilm infections. The nanoparticle-ultrasound combination reduced the antibiotic concentration needed by more than 40-fold and eliminated 100% of bacteria at clinically feasible doses.
Perhaps most importantly, the system proved highly effective against persister cells—dormant bacteria that typically survive treatment and cause recurring infections. Compared with free antibiotics, the nanoparticles reduced the drug concentration needed to eliminate persister cells by 25-fold.
Understanding Ultrasound-Triggered Nanoparticle Delivery Systems
The antibiotic delivery system uses phospholipid-coated nanodroplets synthesized through a procedure based on a clinically approved contrast agent. These nanodroplets were loaded with four different antimicrobials, each with distinct mechanisms against biofilms:
What are nanoparticles?
Nanoparticles are extremely tiny particles, ranging from 1 to 100 nanometers in size. To put this in perspective, human hair is about 80,000-100,000 nanometers thick. At this scale, materials often behave differently than at larger scales, making them useful for specialized applications like drug delivery.
In this technology, The Oxford team created slightly larger nanodroplets (125-250 nm) that are still incredibly small but large enough to carry meaningful amounts of antibiotics. These particles are small enough to penetrate biofilm structures but remain stable until activated.
What are phospholipids?
Phospholipids are specialized fat molecules that makeup cell membranes. Their hydrophilic (water-loving) head and hydrophobic (water-repelling) tails allow them to naturally form bilayers or spherical structures in water.
In this technology, The researchers used phospholipids to create the outer shell of their nanodroplets. This shell provides stability and can be engineered to hold different types of antibiotics depending on whether they’re water-soluble or fat-soluble.
What is perfluorocarbon?
Perfluorocarbons are synthetic compounds where all hydrogen atoms in hydrocarbons have been replaced with fluorine atoms. They have unique properties: they’re liquid at room temperature but can easily become gas when energy is applied, and they don’t mix with water or fat.
In this technology, The core of each nanodroplet contains perfluorocarbon liquid. When ultrasound energy hits these droplets, the liquid rapidly converts to gas, causing the droplet to expand dramatically and then form microbubbles.
What is ultrasound?
Ultrasound refers to sound waves with frequencies higher than humans can hear (above 20 kHz). Medical ultrasound typically uses frequencies between 2 and 15 MHz. These sound waves can travel through soft tissues in the body and be focused at specific locations.
The Oxford team used ultrasound at 3.125 MHz in this technology to trigger their nanodroplets. At this frequency, sound waves can penetrate deep into the body and be precisely focused on infection sites without harming surrounding tissues.
What is acoustic cavitation?
Acoustic cavitation occurs when ultrasound waves create alternating high-pressure (compression) and low-pressure (rarefaction) regions in a liquid. These pressure changes can cause bubbles to form, expand, and sometimes violently collapse, creating local forces that can disrupt nearby structures.
In this technology, when ultrasound hits the nanodroplets, they undergo controlled cavitation—expanding during low-pressure phases and contracting during high-pressure phases. This mechanical action physically disrupts the biofilm matrix.
What are the different types of antibiotics used?
Antibiotics work in various ways to kill bacteria or prevent them from multiplying. Some target bacterial cell walls, others interfere with protein synthesis, and some disrupt bacterial DNA replication.
In this technology, The Oxford team loaded their nanodroplets with four different types of antimicrobials, each with distinct mechanisms:
- Ruthenium complex – A metal-based compound that can damage bacterial membranes
- Azithromycin – Disrupts bacterial protein synthesis and interferes with quorum sensing (how bacteria communicate)
- Besifloxacin – Prevents bacterial DNA replication
- Polymyxin B – Attacks bacterial cell membranes
This multi-pronged approach addresses different aspects of bacterial defence mechanisms.
What are persister cells?
Persister cells are a small subset of bacterial cells that enter a dormant, non-dividing state. In this state, they’re highly tolerant to antibiotics because most antibiotics target active cellular processes. When antibiotic treatment stops, persisters can reawaken and reestablish an infection.
In this technology, The mechanical disruption caused by the expanding nanodroplets helps activate dormant persister cells (making them vulnerable to antibiotics) and deliver high concentrations of antibiotics directly to them. This resulted in a 25-fold reduction in the antibiotic concentration needed to eliminate these typically resistant cells.
How does this technology overcome biofilm resistance?
Biofilms resist antibiotics through multiple mechanisms: the physical barrier of the extracellular matrix, reduced metabolic activity of embedded bacteria, and specialized persister cells.
In this technology, The Oxford solution addresses each defense mechanism:
- Physical barrier: The expanding nanodroplets physically disrupt the protective matrix
- Drug penetration: Antibiotics are delivered directly through the broken matrix
- Cellular uptake: The nanodroplets enhance antibiotic accumulation inside bacterial cells by 11-fold
- Persister targeting: The mechanical stimulation can activate dormant cells while simultaneously delivering antibiotics
This comprehensive approach resulted in a 40-fold reduction in the antibiotic concentration needed to eliminate biofilm infections, potentially transforming how we treat these challenging conditions.
Biofilms are responsible for numerous difficult-to-treat infections, including chronic wounds, urinary tract infections, cystic fibrosis-related lung infections, and acne. The Oxford technology could potentially transform treatment approaches across these conditions.
“Innovative solutions are desperately needed to extend the action of life-saving antibiotics,” notes Professor Stride. “Our findings are very promising, as treatment of chronic infections associated with biofilm production continues to be a challenge in the face of spreading antimicrobial resistance worldwide.”
The methods used in the study were specifically designed for clinical use, which could accelerate the pathway to practical applications in healthcare settings.
Having demonstrated the system’s effectiveness in laboratory studies, the team is now working to develop the nanoparticle manufacturing method so they can be tested clinically as soon as possible.
If the clinical trials are successful, this technology could represent a significant advancement in treating antibiotic-resistant infections, which affect hundreds of millions of people worldwide. By making existing antibiotics more effective against biofilms, the approach could help extend the useful life of current antimicrobial drugs while new ones are being developed.
This innovation is critical in the fight against antimicrobial resistance, which continues to grow as a global health concern. The Oxford team addresses a fundamental challenge in infection treatment by targeting one of the key mechanisms bacteria use to evade antibiotics.
The technology demonstrates how engineering approaches can offer new solutions to medical problems that have proven resistant to conventional pharmaceutical strategies alone. By combining physical disruption with targeted drug delivery, the system works with the body’s natural defences rather than relying solely on chemical intervention.
As antimicrobial resistance continues to spread worldwide, such innovative approaches will be essential to ensuring that infections remain treatable in the future.
TLDR:
- Oxford engineers developed ultrasound-activated nanoparticles that physically break through bacterial biofilms
- The system simultaneously disrupts the protective biofilm matrix and delivers antibiotics directly to the infection site
- Testing showed a 40-fold reduction in the antibiotic concentration needed to eliminate biofilm infections
- The technology was effective against dormant “persister” bacteria that typically cause recurring infections
- The team is now working to develop the manufacturing process for clinical testing
