Photochemical Activation of Bioactive Molecules

Photochemical activation harnesses light to temporally and spatially control the release or activation of bioactive molecules. By appending photoremovable protecting groups (PPGs) to endogenous ligands, lipids or therapeutic agents, researchers can trigger precise uncaging events using ultraviolet, visible or near-infrared (NIR) light. This approach enables interrogation of dynamic processes such as intracellular signalling cascades, membrane lipid dynamics and site-specific drug action with subcellular resolution. Advances in chromophore design, two-photon excitation and energy-transfer strategies have extended activation wavelengths into the biologically benign visible and NIR regions, facilitating in vivo applications. Key challenges include maximising photolysis efficiency, minimising off-target phototoxicity and achieving organelle- or tissue-specific delivery.

Research from Nature Portfolio

Recent studies have demonstrated NIR-triggered prodrug photolysis via a one-step triplet–triplet energy transfer process. By pairing a photosensitiser capable of singlet–triplet absorption with BODIPY-based prodrugs, deep-tissue activation under low-irradiance NIR light yields high release efficiencies. Encapsulation of both photosensitiser and prodrug within a micellar nanosystem has shown effective spatiotemporal drug delivery in aqueous environments, offering promise for photoactivated cancer therapy. Another investigation introduced a sulfonated coumarin cage that anchors lipid mediators exclusively to the outer plasma-membrane leaflet. Live-cell microscopy of uncaging events revealed that precise subcellular release of arachidonic acid differentially modulates calcium oscillations in β-cells and synaptic transmission in neuronal preparations, underscoring the importance of membrane localisation in signalling outcomes.

Photochemical Activation of Bioactive Molecules publication trend

The graph below shows the total number of articles in photochemical activation of bioactive molecules across all publications each year (not limited to Nature Index journals).

Technical terms

Photoremovable protecting group (PPG): A light-cleavable moiety that temporarily masks a bioactive compound and releases it upon irradiation.

Caged compound: A bioactive molecule rendered inactive by covalent attachment of a PPG, which is removed by light to restore function.

Two-photon absorption: A nonlinear optical process in which two photons of lower energy are absorbed simultaneously to induce photochemical release in a confined volume.

Quantum yield: The ratio of released molecules to photons absorbed, quantifying the efficiency of a photochemical reaction.

Singlet–triplet energy transfer: A mechanism by which a photosensitiser in its triplet state transfers energy to a target chromophore, enabling photolysis under longer wavelengths.

References

1. The Road to Quantitative Lipid Biochemistry in Living Cells. Accounts of Chemical Research (2023).
2. Near-infrared light-triggered prodrug photolysis by one-step energy transfer. Nature Communications (2023).
3. Exclusive photorelease of signalling lipids at the plasma membrane. Nature Communications (2015).
4. Strategy for Engineering High Photolysis Efficiency of Photocleavable Protecting Groups through Cation Stabilization. Journal of the American Chemical Society (2022).
5. Visible-to-NIR-Light Activated Release: From Small Molecules to Nanomaterials. Chemical Reviews (2020).