Bold reality check: cholesterol, essential to life, also holds the key to some of our biggest health concerns, and now scientists are learning to control it with light.
Cholesterol is a tiny, water-insoluble lipid present in every cell and crucial for building cell membranes and producing important hormones like estrone and testosterone. Yet its dual nature makes studying it tricky, since its small size makes it tough to observe directly. To study it, researchers often use functional derivatives—molecules that imitate cholesterol but carry chemical tags that let scientists see and track them.
In a study published in the Journal of the American Chemical Society, Michael Zott, a Beckman Postdoctoral Fellow at the University of Pennsylvania, and his team, guided by postdoctoral adviser Dirk Trauner, created a new class of cholesterol surrogates equipped with light-sensitive components. These photocholesterols change shape when illuminated, enabling researchers to toggle cholesterol’s biological activity on and off.
This light-controlled approach opens the door to advanced therapeutics, allowing drugs to be activated deep inside the body where conventional controls fall short. The researchers aim to use light that can penetrate the skin to reach specific organs, enabling precise timing and location of drug activation.
“One advantage of using light to trigger these geometric changes is that certain wavelengths can penetrate tissues quite deeply,” explains Trauner, co-senior author and Penn Integrates Knowledge University Professor. “This enables spatiotemporal control: a patient could take a medicine systemically, and a focused beam of light would turn the molecule on only in a targeted area.”
Interestingly, the photocholesterols did not behave exactly like a universal stand‑in for cholesterol. Instead of a perfect, all-purpose mimic, some photocholesterols showed strong preferences for certain transport proteins. In one noteworthy case, a candidate emerged as a potential first selective inhibitor of two poorly understood sterol transport proteins, ORP1 and ORP2.
“This work has already yielded new discoveries,” says Luca Laraia of the Technical University of Denmark, co-senior author. “We now have the first photoswitchable inhibitors for ORP1 and ORP2, proteins that are clearly important for cholesterol balance but whose functions aren’t fully understood. This will help us uncover their biological roles.”
Zott adds, “By identifying molecules that selectively target these proteins, we can begin to develop tools to turn them off or on with precision. That will illuminate their functions in health and disease.”
Looking ahead, the team plans to use light’s precision to map when and where key sterol transport proteins move cholesterol within cellular models under normal and disease-like conditions. They also intend to apply the same computational design approach to craft light-controlled versions of other lipids, with long-term goals such as optimizing lipid nanoparticle formulations for light-controlled mRNA delivery and designing systemic therapies that can be activated locally with focused light for exact spatiotemporal control.
“Cholesterol sits at the center of biology and underpins tech like the lipid nanoparticles used in modern vaccines,” notes Zott. “A light-controlled cholesterol model lets us explore and potentially improve these crucial processes.”
