Major Progress in the Development of New Medications Against Dangerous Fungal Infections
This week, our study was published and showcased on the back cover of the journal Nanoscale, demonstrating a breakthrough: the first in vivo success of siRNA therapy against Aspergillus fumigatus, a human pathogenic fungus. By packaging small interfering RNAs with Amphotericin B in anionic liposomes, we specifically targeted critical fungal genes, effectively halting pathogen growth. This innovative RNAi approach marks a significant advancement in developing next-generation antifungal treatments.
Nanomedicine with siRNA shows first effectiveness against the human-pathogenic fungus Aspergillus fumigatus.
Fungal infections are on the rise globally. According to a study by the Manchester Fungal Infection Group, in 2022, approximately 6.5 million people were infected by a pathogenic fungus, and about 3.8 million died as a result – nearly twice as many as in 2012. Even with medications, known as antifungals, the mortality rate for invasive infections caused by the mold Aspergillus fumigatus is as high as 85%. As resistant fungal strains increase, treatment becomes more difficult, and new therapies are urgently needed. A team from the University Medicine Würzburg, Germany, has now found a promising strategy against fungal infections.
RNAi Combined with Optimized Delivery Technology
To specifically target the mold Aspergillus fumigatus, the researchers combined an RNAi approach with optimized delivery technology from nanomedicine. Ribonucleic acid (RNA) plays a central role in the implementation of genetic information. RNA interference (RNAi) acts like a ‘gene switch,’ selectively silencing specific genes. It uses specialized RNA molecules, such as small interfering RNA (siRNA) or microRNA (miRNA), to block genetic instructions needed for protein production.
“Our study builds on the discovery of RNA interference, for which the Nobel Prize in Medicine was awarded in 2006. While siRNA therapies have already been used for genetic diseases, our work is the first successful application of this technology against a human pathogenic fungus in infection models. The genetic differences between fungi and humans offer unique therapeutic opportunities,” explains first author and former postdoctoral fellow of the Beilhack lab Dr. Yidong Yu.
New strategy to treat A. fumigatus infections with anionic liposomes loaded with small interfering RNAs (siRNAs) and low doses of Amphotericin B facilitating fungal cell entry to specifically inhibit three essential key genes for fungal growth.
Technological Breakthrough in Fungal Control
One of the biggest challenges was packaging the siRNA in a way that it could penetrate the thick cell wall of the fungus. “The trick was to combine anionic liposomes with small amounts of the antifungal drug Amphotericin B,” reports co-first author Theresa Vogel about her doctoral thesis of the group of Dr. Krystyna Albrecht and Prof. Jürgen Groll at the Institute of Functional Materials in Medicine and Dentistry (FMZ) at Würzburg University Hospital. Anionic liposomes are tiny fat vesicles with a negative charge. Amphotericin is a proven antifungal medication that makes the fungal cell walls more permeable, allowing the siRNA to penetrate the fungal cells and specifically inhibit three crucial genes necessary for fungal growth. The concept was developed an interdisciplinary collaboration between Dr. Krystyna Albrecht and Prof. Jürgen Groll and the Beilhack lab. Yidong Yu and Theresa Vogel tested various nanoparticle strategies until the breakthrough was achieved. To further advance the development of novel antifungal strategies Dr. Yidong Yu was recently awarded a prestigious two-year fellowship from the Japan Society for the Promotion of Science (JSPS), supported by the Alexander von Humboldt Foundation, to continue her research in a leading global research group on silkworms.
Fungal Infections and Resistance to Common Antifungals Are Increasing
“The results of our study show that our chosen method significantly reduces fungal growth in infection models and as a proof-of-concept demonstrates the effectiveness of siRNA as a promising tool against fungal infections in humans,” summarizes senior author Prof. Andreas Beilhack from the Department of Medicine II of UKW. “The study is particularly significant because infections with Aspergillus fumigatus are increasing globally, and resistance to common antifungals is becoming more common. The siRNA strategy could not only be used against Aspergillus fumigatus but also against other dangerous fungal pathogens.”
Our study was funded by the German Research Foundation (DFG) within our research consortia “FungiNet” (SFB/TRR 124) of the German universities Jena and Würzburg and “Biofabrication” (SFB/TRR 22 5) of the Bavarian universities Bayreuth, Erlangen and Würzburg and published in the journal Nanoscale. The groundbreaking research is highlighted on the cover of the print edition underscoring its scientific relevance and to transform the treatment of life-threatening fungal infections.