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Revolutionizing Drug Design with Light-Activated Tiny Machines

Calcium signaling is a key mechanism through which cells “talk” to one another to coordinate vital biological processes such as immune activation, muscular contraction, hormone release, neuronal firing, and digestion.

Revolutionizing Drug Design with Light-Activated Tiny Machines
Jacob Beckham is a Rice U. chemistry graduate student and a lead author on the study. Image Credit: Gustavo Raskosky/Rice University

In a recent study published in Nature Nanotechnology, researchers from Rice University revealed a potent new method for directing cellular activity by using light-activated molecular machines to create intercellular calcium wave signals.

People with heart difficulties, digestive issues, and other conditions could benefit from enhanced therapies with the help of this technology.

Most of the drugs developed up to this point use chemical binding forces to drive a specific signaling cascade in the body. This is the first demonstration that, instead of chemical force, you can use mechanical force—induced, in this case, by single-molecule nanomachines—to do the same thing, which opens up a whole new chapter in drug design.

Jacob Beckham, Study Lead Author and Graduate Student, Rice University

To trigger a calcium-signaling response in smooth muscle cells, researchers used small-molecule actuators that rotate when triggered by visible light.

Many of the body’s key muscles are not under conscious control in humans: Smooth muscle tissue lines the veins and arteries, managing blood pressure and circulation; smooth muscle lines the lungs and intestines, and is involved in digesting and breathing.

The ability to intervene in these processes with a molecular-level mechanical stimulus could be game-changing.

Beckham has shown that we can control, for example, cells’ signaling in a heart muscle, which is really interesting.

James Tour, T. T. and W. F. Chao Professor of Chemistry, Rice University

He added, “If you stimulate just one cell in the heart, it will propagate the signal to the neighboring cells, which means you could have targeted, adjustable molecular control over heart function and possibly alleviate arrhythmias.”

The molecular machines, activated by quarter-second light pulses, allowed scientists to manipulate calcium signaling in a cardiac myocyte cell culture, forcing the quiescent cells to ignite.

Beckham stated, “The molecules essentially served as nano-defibrillators, getting these heart muscle cells to start beating.

The capacity to regulate cell-to-cell communication in muscle tissue could prove helpful for the treatment of a variety of diseases characterized by dysfunctional calcium signaling.

Tour added, “A lot of people who are paralyzed have huge digestive problems. It would be a big deal if you could alleviate these issues by causing those relevant muscles to fire without any kind of chemical intervention.

The fresh-water polyp, or Hydra vulgaris, underwent whole-body contraction as a result of the molecule-sized devices’ activation of the same calcium-based cellular signaling process in a living organism.

This is the first example of taking a molecular machine and using it to control an entire functioning organism,” Tour added.

The type and strength of the mechanical stimulation affected the cellular response: In contrast to slower rates and multidirectional rotation, fast, unidirectionally revolving molecular machines produced intercellular calcium wave signals.

Furthermore, the strength of the cellular reaction can be altered by varying the light’s intensity.

Tour further stated, “This is mechanical action at the molecular scale. These molecules spin at 3 million rotations per second, and because we can adjust the duration and intensity of the light stimulus, we have precise spatiotemporal control over this very prevalent cellular mechanism.

The Tour lab has demonstrated in earlier studies that light-activated molecular machines can be used to combat cancer cells, infectious bacteria that are resistant to antibiotics, and harmful fungi.

Beckham noted, “This work expands the capabilities of these molecular machines in a different direction. What I love about our lab is that we are fearless when it comes to being creative and pursuing projects in ambitious new directions. We are currently working towards developing machines activated by light with a better depth of penetration to really actualize the potential of this research. We are also looking to get a better understanding of molecular-scale actuation of biological processes.

The DEVCOM Army Research Laboratory (Cooperative Agreement W911NF-18-2-0234), the Robert A. Welch Foundation (C-2017-20190330), the National Science Foundation Graduate Research Fellowship Program, the Discovery Institute, and the EU’s Horizon 2020 (Marie Sklodowska-Curie grant agreement 843116) provided funding for the study.

Molecular motor-induced calcium wave oscillation and beating motion in cardiac myocyte cell

Molecular motor-induced "beating" motion and calcium wave oscillation in cardiac myocyte cells (stimulation applied at the 30 second mark ¾ timestamp in top left corner). (Video edited by Brandon Martin/Rice University)

Journal Reference:

Beckham, J. L., et al. (2023) Molecular machines stimulate intercellular calcium waves and cause muscle contraction. Nature Nanotechnology. doi:10.1038/s41565-023-01436-w.

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