A team of researchers at Switzerland’s University of Basel have developed artificial organelles that have been successfully introduced into living cells and activated in response to intracellular redox changes.
According the researchers, this is the first time that this has been achieved and could pave the way for the development of highly personalized therapies.
The artificial organelles are nanospheres with compartmentalized active compounds including proteins, enzymes and catalysts. The artificial organelles were shown to be activated by glutathione levels in vitro, and survived introduction into zebrafish embryos and continued to function correctly in vivo.
To ensure control over the enzyme activity, the researchers introduced genetically modified porin channels in the outer membrane of the polymersome artificial organelles which act as redox-responsive gates. When the levels of glutathione in the cells is low, the protein gates remain closed. As glutathione levels increase and a threshold level is passed, the gates open and let low molecular weight molecules in. The researchers incorporated the enzyme – horseradish peroxidase – in the organelles which was activated by redox changes inside the cells. The activity of the enzyme is only triggered when specific molecules pass through the outer membrane of the organelles.
The researchers explain that “This approach mimics pathways of metabolism regulation, where proteins within the membranes of natural cell organelles are irreversibly activated or deactivated on demand.”
After demonstrating their polymersome artificial organelles worked in vitro, they were introduced into zebrafish embryos. Since the embryos are transparent, it was easy to monitor enzyme activity using fluorescent dye tags. The artificial organelles were taken up by macrophages and the enzyme activity was triggered by hydrogen peroxide produced by the macrophages after it passed into the artificial organelles through the protein gates.
By altering the compounds in the compartmentalized artificial organelles and incorporating protein gates that respond to different intracellular stimuli, the artificial organelles could have many clinical applications, such as patient-oriented protein therapy.
The research is detailed in the paper – Biomimetic artificial organelles with in vitro and in vivo activity triggered by reduction in microenvironment – was recently published in Nature Communications.