Scientists at Huazhong University of Science and Technology have developed a nanophotosynthetic therapy (NPT) platform that they hope could one day help to protect against brain damage in stroke patients by generating the oxygen needed to keep neurons in the affected area alive. The therapeutic approach involves delivering the photosynthetic blue-green algae Synechococcus elongatus directly into the brain, together with nanoparticles that can convert tissue-penetrating near-infrared (NIR) light into the visible spectrum light that S. elongatus needs to photosynthesize and produce oxygen.

Reporting on development of their platform in Nano Letters, the investigators said proof-of-concept tests in a rodent model of stroke demonstrated that NPT improved oxygenation of infarct brain tissue, reduced the volume of damage, promoted the survival of neurons, and enhanced new blood vessel formation, “… thus collaboratively leading to significant recovery of neuronal functions and animal-level behavioral performance.” Research leads Lin Wang, PhD, Zheng Wang, PhD, and Guobin Wang, PhD, and colleagues describe the technology in a paper titled, “Oxygen-Generating Cyanobacteria Powered by Upconversion-Nanoparticles-Converted Near-Infrared Light for Ischemic Stroke Treatment.”

Stroke kills five million people worldwide every year, according to World Health Organization figures cited by the authors. Millions more people with stroke do survive, but they often experience disabilities, such as difficulties with speech, swallowing or memory. The most common type of stroke, ischaemic stroke, is caused when blood vessels leading to the brain become blocked, which starves the brain tissue of oxygen, and also results in a build up of carbon dioxide. The resulting effects, including acidosis, nitrosative and oxidative stress, and mitochondrial dysfunction, lead to irreversible neuronal death, the team continued.

The best way to prevent permanent brain damage from this type of stroke is to dissolve or surgically remove the blockage as soon as possible. However, these options only work within a narrow time window after the stroke happens, and can be risky. “Clinically, intravenous thrombolysis (IVT) and intra-arterial thrombectomy (IAT) are two available treatments for revascularization to rescue neurons,” the authors wrote. “However, less than 5% of stroke patients benefit from these therapies due to the narrow treatment window (4.5 h for IVT and 6 h for IAT after stroke), and increased risk of intracranial hemorrhage.”

Because lack of oxygen—hypoxia—is the primary crisis after stroke, finding a treatment that can deliver oxygen to the affected areas might help to protect neurons. Oxygen-carrying biomaterials have been investigated as one option, but as the investigators pointed out, “… their limited oxygen-carrying capacity and inability of reducing the accumulated carbon dioxide impede their development into therapeutics”. More intriguingly, the team continued, scientists have recently harnessed the photosynthetic blue-green algae (also known as a cyanobacterium) S. elongatus, to increase tissue oxygenation and improve cardiac function in heart tissues. Another study has demonstrated the use of a different cyanobacterium to increase oxygen levels in hypoxic areas of tumors. The researchers thus reasoned, “With the ability of persistently producing oxygen and consuming carbon dioxide in the light, S. elongatus might overcome the aforementioned limitations of oxygen-carrying biomaterials and serve as an active oxygen-generating, carbon dioxide-consuming component.”

One challenge, however, is that the visible light needed for S. elongatus to photosynthesize can’t penetrate the skull. The team acknowledged, “… another practical challenge facing stroke photosynthetic therapy lies in how to effectively provide light to drive photosynthesis in S. elongatus within cerebral ischemia regions underneath a skull.”

Near-infrared light can pass through tissues, but this wavelength of light can’t directly power photosynthesis. And what are known as “up-conversion” nanoparticles (UCNPs)— which are often used for imaging—can absorb near-infrared photons and emit visible light. The Huazhong University of Science and Technology team combined neodymium up-conversion nanoparticles, NIR light, and the S. elongatus cyanobacteria to develop an NPT platform that could feasibly be used to help deliver oxygen to the brain.

Initial studies using cultured mouse neurons showed that the NPT technology could reduce the numbers of cells that died after oxygen and glucose deprivation. “… upon exposure of skull-obstructed NIR, the combination of S. elongatus and UCNPs protected the co-cultured cells by consuming the accumulated carbon dioxide and simultaneously producing oxygen,” they wrote.

Brain slices of mice that received nano-photosynthetic therapy (right) have fewer damaged neurons, shown in green, than control mice (left). [Adapted from Nano Letters 2021, DOI: 10.10.21/acs.nanolett.1c00719]

The team then injected the S. elongatus blue-green algae and UCNPs directly into the brains of mice with blocked cerebral arteries, and exposed the animals to near-infrared light. They found that the treatment reduced both numbers of dying neurons, and the volume of infarct brain tissue “… these results reveal the effectiveness of NPT in reducing the number of dying neurons,” the team wrote. Mice that received NPT also demonstrated improved post-stroke neurological function, measured using a modified Neurological Severity Score that reflects performance of motor, sensory, reflex and balance. Tests showed that NPT significantly improved motor coordination and limb control in the stroke-affected animals, indicating recovered dexterity. “Collectively, these results provide strong evidence demonstrating that the NPT promotes cerebral functional recovery in preclinical stroke-stricken animals,” the investigators stated.

Encouragingly, nanophotosynthetic therapy in addition promoted the growth of new blood vessels around the infarct areas of the brain. “… angiogenesis appeared to be promoted in stroke-stricken brain tissues of the NPT-treated mice, which might partly account for significantly recovered brain functions,” they pointed out. “Consistently, NPT treated mice displayed the enhanced vascular density in the peri-infarct, possibly due to dual functional roles of NPT in promoting angiogenesis and protecting the remaining vascular network from stroke-related injury.”

The described NPT platform is still at the animal testing stage and further work will be needed to optimize the system for potential human use, but the researchers maintain that it shows promise to advance someday toward human clinical trials. “This work represents the first study utilizing S. elongatus and UCNPs under NIR irradiation in the context of stroke treatment,” they noted. “Such a NIR-driven oxygen-generating biosystem might be a valuable clinical alternative for stroke therapy.”

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