Immune Cells Get Transformed into Fungus-Fighting Nanoparticles

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• Liezel Labios - [email protected]

Topics covered:

• Antifungal Nanoparticles
• Candida Albicans
• Macrophage Cell Membranes

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Tiny particles made from the membranes of human immune cells could offer a promising new way to fight fungal infections that are becoming harder to treat. Engineers at the University of California San Diego created antifungal nanoparticles that target Candida albicans, a fungus responsible for oral and vaginal yeast infections as well as life-threatening bloodstream infections. In mice with severe Candida infections, the nanoparticles greatly reduced the amount of fungus in major organs and significantly improved survival.

The research, published in Cell Biomaterials, was led by Liangfang Zhang, professor in the Aiiso Yufeng Li Family Department of Chemical and Nano Engineering at the UC San Diego Jacobs School of Engineering, who also holds the Joan and Irwin Jacobs Chancellor's Endowed Chair in Innovations for Engineering in Medicine.

Antifungal medications today typically target specific parts of a fungal cell and can lose effectiveness as fungi evolve resistance. The nanoparticles that Zhang and his team developed use a more potent strategy. They physically damage fungal cells and, at the same time, boost the body's natural immune defenses.

To create the nanoparticles, researchers isolated the outer membranes of human macrophages, a type of white blood cell that serves as one of the body's first lines of defense against infection. They broke up the cell membranes into tiny pieces and fused them onto disc-shaped nanoparticles made from a biodegradable polymer. These so-called nanodiscs are built from real macrophage cell membranes rather than synthetic materials, so they retain the same proteins that macrophages use to recognize and attack fungi. They essentially behave like miniature versions of the body's own immune cells themselves, which also allows them to evade attack by the immune system.

Zhang's team chose macrophage membranes because they are covered with receptors that naturally recognize Candida. By preserving those receptors, the nanodiscs can identify and attach to fungal cells more effectively than nanoparticles made from other cell types, such as red blood cells.

Once attached, the nanodiscs weaken the fungal cell's protective outer membrane until tiny openings form. As the membrane breaks down, the cell's contents leak out and unwanted substances seep in, ultimately killing the fungus. Because this strategy physically damages the fungal cell rather than targeting a specific molecule, researchers believe it may be much harder for the fungus to evolve resistance.

This particular fungus-fighting ability all comes down to size. Each nanodisc measures about 10 to 20 nanometers in size, roughly 1,000 times smaller than a macrophage. That tiny size allows the nanodiscs to fuse directly with the fungal cell membrane and destabilize it - something a full-sized macrophage cannot do. In the body, macrophages attack fungal cells by engulfing them. But Candida has evolved ways to survive inside macrophages and escape, which makes it harder to keep an infection from spreading. The nanodiscs help the immune system regain the upper hand. By damaging fungal cells, the nanodiscs make them more susceptible to clearance by the body's macrophages.

The nanodiscs provide another countermeasure. Candida suppresses macrophages from producing natural fungus-fighting chemicals, and the nanodiscs more than reverse that suppression; they enable macrophages to produce higher levels of these antifungals. They also prevent Candida from forming biofilms, which shield fungal cells from drugs and the immune system.

The researchers administered the nanodiscs to mice with severe bloodstream infections caused by Candida. Treated mice had far less fungus in their heart, kidneys, lungs and spleen. Their survival also improved significantly compared to untreated mice. Higher doses provided greater protection. In some cases, all treated mice survived.

The treatment was also effective when administered before infection. This finding suggests that the nanodiscs could potentially be used to protect against fungal infections.

Next steps include further evaluating the antifungal potency of these cellular nanodiscs against a broader range of highly pathogenic fungal species.

Full study: "Cell membrane-derived nanotherapeutic for combating Candida albicans infections." Co-first authors of the study are Zhidong Zhou, Kailin Feng and Lei Sun, all at UC San Diego.

This work was supported by the Defense Threat Reduction Agency Joint Science and Technology Office for Chemical and Biological Defense (award number HDTRA1-24-1-0019).