A bacteriophage-inspired nanomotor uses ultrasound-activated antibiotics and self-propulsion to penetrate lung biofilms and eliminate drug-resistant pneumonia bacteria with high precision and therapeutic effect.
(Nanowerk Spotlight) Lungs infected by biofilm-forming bacteria can become nearly untreatable, even with access to modern antibiotics. These infections are not only physically embedded in dense, sticky matrices secreted by bacteria, but they also evolve to resist the very drugs designed to kill them. Doctors trying to clear such infections—especially those caused by Klebsiella pneumoniae, a bacterium notorious for developing multidrug resistance—often face failure, relapse, or even fatal outcomes.
Standard treatments struggle to reach bacteria hiding behind biofilm barriers. Once established, these microbial fortresses shield the pathogens from immune attacks and degrade most chemical therapies before they can take effect.
What has held back progress isn’t a lack of antibacterial agents but an inability to deliver them with precision and force inside hostile microenvironments. Biofilms are chemically reactive, acidic, oxygen-deprived, and laden with hydrogen peroxide—all conditions that render conventional delivery systems ineffective.
Strategies like nanoparticle encapsulation or passive diffusion through tissue have been explored but tend to fall short when bacteria mount both physical and biochemical defenses. Meanwhile, inspiration from nature—particularly bacteriophages, viruses that drill into bacterial cells with mechanical precision—has pointed researchers toward entirely new forms of attack.
Advances in nanoscale fabrication and bioresponsive materials have now made it possible to engineer synthetic systems that mimic phage-like invasiveness. By combining mechanical motion, chemical targeting, and external control through ultrasound, a new generation of engineered nanomaterials is emerging. These platforms don’t just carry drugs; they actively penetrate and disrupt bacterial biofilms while responding to the unique chemistry of infection sites.
The study, led by Naiyue Zhang and colleagues, introduces a self-propelling nanoparticle designed to penetrate and dismantle biofilms formed by multidrug-resistant Klebsiella pneumoniae (MDR-KPN). The researchers engineered a two-part nanoparticle—known as a Janus particle due to its asymmetry—composed of two functionally distinct regions. One side consists of hollow mesoporous Prussian blue, a porous material that stores and releases the antibiotic lomefloxacin. The other side is made of copper oxide, which reacts with hydrogen peroxide in the infection site to generate oxygen. This oxygen formation propels the nanomotor forward, helping it actively navigate through the dense structure of a biofilm.
Illustration of how the nanomotor is built and how it works to overcome drug-resistant pneumonia bacteria. a) Steps for creating a two-part nanomotor that mimics biological systems and physically disrupts bacterial membranes. b) How the nanomotor uses both mechanical force and chemical action to break down biofilms and kill bacteria. (Image: Reprinted with permission by Wiley-VCH Verlag) (click on image to enlarge)
The system is designed to operate through a combined mechanism. First, it physically disrupts the biofilm by moving through it with force generated from oxygen bubbles. Then, once ultrasound is applied externally, the Prussian blue side releases lomefloxacin. This antibiotic not only inhibits bacterial DNA gyrase, a key enzyme in DNA replication, but also produces reactive oxygen species under ultrasound. These molecules, especially singlet oxygen, further damage bacterial structures and DNA, increasing the chance of complete eradication.
The researchers found that the asymmetric hollow design increased drug loading efficiency and responsiveness to acidic conditions typical of biofilm environments. The hollow architecture allowed more drug to be stored and released in response to environmental cues. The system’s speed and motion were shown to depend on hydrogen peroxide concentration, which is elevated in infected tissue. Higher peroxide levels led to faster movement, more effective penetration, and improved biofilm disruption.
Tests in laboratory settings confirmed the particle’s ability to infiltrate biofilms. Nanoparticles quickly entered and accumulated within established MDR-KPN biofilms, especially when hydrogen peroxide was present to fuel their propulsion. When ultrasound was applied, biofilms were disrupted more thoroughly, and bacterial counts fell significantly compared to treatments with antibiotics or ultrasound alone.
To examine how the treatment affected bacterial function, the researchers used transcriptomic analysis, which compares gene expression before and after treatment. They observed widespread disruption in bacterial metabolic pathways, including genes involved in DNA repair, biofilm formation, membrane transport, and oxidative stress response. Bacteria exposed to the nanomotor system activated stress pathways in an attempt to compensate, but these responses appeared insufficient. Genes that support biofilm structure and resistance were suppressed, while stress-related genes showed marked upregulation.
Animal testing provided further support. Mice with MDR-KPN-induced lung infections received the nanomotor treatment via aerosol inhalation. Some groups also received ultrasound therapy to trigger the antibiotic release. The particles accumulated in lung tissue and were later cleared through the kidneys. Mice that received the combined treatment had higher survival rates, lower bacterial counts, and reduced signs of lung damage. Lung tissue from these mice showed less inflammation, less fluid buildup, and fewer lesions compared to mice treated with antibiotics or ultrasound alone.
Importantly, the researchers also evaluated the safety of the system. Blood chemistry remained within normal limits, and no signs of toxicity or tissue damage were found in major organs after treatment. The particles did not cause red blood cell damage or affect immune cell counts. These results suggest that the nanomotor platform can be used safely in vivo, with minimal side effects.
The integration of mechanical penetration and ultrasound-triggered antibiotic action into a single system makes this approach distinct. Rather than relying on passive diffusion, the particle moves on its own using the infection’s chemistry as fuel. It delivers antibiotics directly into the biofilm and triggers their release on demand, allowing both physical and chemical mechanisms to work in tandem.
While further studies will be needed to scale and validate the system in clinical contexts, the work offers a modular strategy for treating difficult bacterial infections. Because the components—copper oxide, Prussian blue, and lomefloxacin—can be modified or replaced, similar systems could potentially be adapted for other types of resistant bacteria or infection sites. The approach also opens avenues for combining mechanical nanodevices with other stimulus-responsive drugs or immune modulators.
By replicating the targeted precision of bacteriophages and integrating it with controlled drug release, the researchers have constructed a system that addresses key failures of traditional antibiotic therapy. The study demonstrates that well-designed nanomaterials can navigate and disrupt bacterial biofilms, providing a flexible and scalable tool for combating antibiotic resistance in settings where older treatments are no longer sufficient.
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