A University at Buffalo team has engineered an inhalable nanoparticle form of a key tuberculosis drug that targets the lungs directly. The approach could cut treatment from daily pills to weekly doses and reduce side effects.
A research team from the University at Buffalo’s Jacobs School of Medicine and Biomedical Sciences has developed an inhalable tuberculosis treatment that could transform how one of the world’s deadliest infectious diseases is managed.
Instead of swallowing daily pills for months, future TB patients might one day breathe in a mist of tiny drug-loaded particles just once a week — and get more medicine where it is needed most: deep in the lungs.
The work, published in the journal Antimicrobial Agents and Chemotherapy, focuses on rifampin, a cornerstone TB drug that is powerful but hard on the body when taken by mouth.
“TB is still one of the world’s deadliest infectious diseases, even though it can be cured. Treatment takes many months and involves multiple drugs that can cause serious side effects,” senior author Jessica L. Reynolds, an associate professor of medicine in the Jacobs School, said in a news release. “Because of this, many patients struggle to finish treatment, which leads to treatment failure and drug-resistant TB.”
Standard TB therapy typically requires multiple drugs taken daily for at least six months. Patients often feel better long before the regimen is over, making it tempting to stop early. At the same time, the drugs can cause serious problems, including liver damage. When people do not complete treatment, the bacteria can survive and evolve into drug-resistant strains that are much harder and more expensive to treat.
Rifampin is a prime example of this trade-off. It is highly effective against TB bacteria but can injure the liver and does not deliver enough drug to the lungs when taken orally. Much of the dose is processed by the liver and distributed throughout the body instead of concentrating at the site of infection.
To solve that problem, the UB team designed a new delivery system: inhalable nanoparticles that carry rifampin directly into the lungs.
The particles have a biodegradable core that holds rifampin and slowly breaks down over time. Around that core is a coating that helps the particles stick to and be taken up by macrophages, the immune cells that TB bacteria use as a hiding place. On the surface, the researchers added a natural molecule that both improves uptake by immune cells and boosts immune activity.
“These particles are specially built to go straight to the lungs and be taken up by lung immune cells called macrophages, which are where TB bacteria hide,” added first author Hilliard L. Kutscher, a research assistant professor of medicine. “They are designed to slowly release rifampin over time, to stimulate the immune system to better fight TB and to reduce drug exposure to the rest of the body, lowering side effects.”
Because the particles are inhaled, they bypass the digestive system and deliver rifampin directly into lung tissue. The slow-release design means the drug can stay in the lungs longer, potentially allowing for once-weekly dosing instead of daily pills.
To test the approach, the researchers used two different mouse models of TB. One model represented a more typical lung infection, while the second was a severe form that closely mimics the extensive lung damage seen in human TB and is more difficult to treat.
“Using both models makes the results more reliable and relevant to human disease,” Reynolds added, allowing the team to see how the therapy performed across a range of disease severity.
In both models, the inhaled nanoparticles delivered rifampin far more effectively to the lungs than daily oral dosing.
“Compared to taking rifampin by mouth every day, the inhaled nanoparticles kept higher levels of the drug in the lungs for much longer — up to a week after a single dose,” added Reynolds.
All experiments involving Mycobacterium tuberculosis, the bacterium that causes TB, were carried out in a certified Biosafety Level 3 laboratory, which is required for TB research nationwide and includes strict safety and containment measures.
The findings point to a future in which TB treatment could be both simpler and safer.
“The work highlights the potential of long-acting inhaled medicines to simplify TB therapy,” Reynolds added. “Reducing treatment frequency could improve adherence, lower side effects and make TB care more accessible worldwide,” especially in regions where daily clinic visits or consistent access to medication are difficult.
She also emphasized the broader implications of the study.
“These findings support continued development of inhalable, long-acting TB therapies as a promising strategy to improve treatment outcomes and reduce the global impact of tuberculosis,” she said.
The next phase of the research will focus on how this nanoparticle system can be combined with other standard TB antibiotics. TB is always treated with multiple drugs at once to prevent resistance, so any new delivery method must fit into combination therapy.
The potential impact of the inhalable rifampin system extends beyond TB, according to co-author Patrick O. Kenney, a clinical assistant professor of pediatrics.
“Rifampin is not just a TB drug; it is also a key medication for other serious lung infections caused by non-tuberculous mycobacteria, such as Mycobacterium kansasii and Mycobacterium xenopi, which are increasingly recognized in the U.S.,” Kenney said in the news release. “These infections often affect people with chronic lung disease and can be difficult to treat.”
These non-tuberculous mycobacterial infections often require long, complex treatment regimens, and rifampin’s interactions with other drugs can limit its use. When taken orally, rifampin strongly activates liver enzymes that break down many medications, including macrolide antibiotics such as azithromycin and clarithromycin, which are central to treating certain lung infections.
“One major limitation of rifampin is that when taken orally, it strongly activates liver enzymes and this reduces the effectiveness of other important antibiotics, such as azithromycin and clarithromycin, which are cornerstones of therapy for Mycobacterium avium/intracellulare complex (MAC) lung disease,” Kenney added. “Because of this interaction, rifampin is often avoided, even when it could otherwise help.”
By targeting rifampin to the lungs and limiting how much reaches the bloodstream, inhalable nanoparticles could reduce these harmful drug-drug interactions while still delivering high concentrations of the drug where it is needed.
“That opens the door to using rifampin more effectively in a broader range of pulmonary mycobacterial diseases — not just TB,” added Kenney.
The project also involved student researchers at UB, highlighting the role of hands-on research training in tackling global health challenges.
While the current study was conducted in mice, the results lay important groundwork for future preclinical and clinical testing. If the approach proves safe and effective in humans, inhalable, long-acting TB therapies could help patients around the world complete treatment, curb drug resistance and bring the global TB burden closer to an end.