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Smart molecular designs and applications of activatable organic photosensitizers

Nature Reviews Chemistry volume 9, pages 46–60 (2025)Cite this article

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Abstract

Photodynamic therapy (PDT) — which combines light, oxygen and photosensitizers (PS) to generate reactive oxygen species — has emerged as an effective approach for targeted ablation of pathogenic cells with reduced risk of inducing resistance. Some organic PS are now being applied for PDT in the clinic or undergoing evaluation in clinical trials. A limitation of the first-generation organic PS was their potential off-target toxicity. This shortcoming prompted the design of constructs that can be activated by the presence of specific biomolecules — from small biomolecules to large enzymes — in the target cells. Here, we review advances in the design and synthesis of activatable organic PS and their contribution to PDT in the past decade. Important areas of research include novel synthetic methodologies to engineer smart PS with tuneable singlet oxygen generation, their integration into larger constructs such as bioconjugates, and finally, representative examples of their translational potential as antimicrobial and anticancer therapies.

Key points

  • Activatable organic photosensitizers (PS) are designed for targeted photodynamic therapy (PDT), reducing off-target toxicity by activating only at disease sites.

  • Chemical activation strategies include pH-responsive, redox-mediated, and enzyme-activatable PS, enhancing selectivity and efficacy in anticancer and antibacterial treatments.

  • Near-infrared (NIR) PS improve tissue penetration and targeting for clinical translatability, with modifications such as extended conjugation and heavy atom inclusion to increase the excitation wavelengths.

  • Successful biomedical applications demonstrate the potential of activatable PS in treating cancers and infectious diseases, with ongoing challenges in clinical adaptation.

  • Future directions focus on optimizing PS formulations for better biodistribution, developing NIR PS for deeper tissue penetration, and exploring sonodynamic activation.

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Fig. 1: Biomarkers within the tumour microenvironment can be harnessed for activatable photodynamic therapy.
Fig. 2: Activation mechanisms behind the differential behaviour of organic PS in their inactive and active states.
Fig. 3: Electrostatic and metabolic labelling as targeting strategies for bacterial ablation in antimicrobial photodynamic therapy.
Fig. 4: Clinical translation with NIR excitation and intelligent formulation designs.
Fig. 5: Chemical strategies to modulate ICT and PS activity in NIR hemicyanines.

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Acknowledgements

The authors acknowledge funding from the Medical Research Council (MR/R01566X/1), the Engineering and Physical Sciences Research Council (EP/W015706/1, to M.V.), an ERC Consolidator Grant (DYNAFLUORS, 771443, to M.V.), the National Research Foundation of Korea (CRI project no. 2018R1A3B1052702, to J.S.K.), the Prestigious DBT-Ramalingaswami Fellowship (BT/RLF/Re-entry/59/2018, to A.S.) and SERB (CRG/2021/0022476, to A.S.). The authors acknowledge BioRender.com for the assistance with figure creation.

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  1. These authors contributed equally: Eleni Nestoros, Amit Sharma.

Authors and Affiliations

  1. Centre for Inflammation Research, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, UK

    Eleni Nestoros & Marc Vendrell

  2. IRR Chemistry Hub, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, UK

    Eleni Nestoros & Marc Vendrell

  3. Amity School of Chemical Sciences, Amity University Punjab, Mohali, India

    Amit Sharma

  4. Department of Chemistry, Korea University, Seoul, Korea

    Eunji Kim & Jong Seung Kim

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  1. Eleni Nestoros
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  2. Amit Sharma
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  4. Jong Seung Kim
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Contributions

E.N. and A.S. contributed equally to this work and were responsible for researching data for the article. E.N. and M.V. discussed the content and wrote the article with contributions from A.S., E.K. and J.S.K.

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Correspondence to Jong Seung Kim or Marc Vendrell.

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Glossary

Activatable fluorophores

Fluorescent molecules whose emission varies in response to biological or chemical stimuli.

Bioorthogonal reactions

Chemical reactions that occur inside living systems without interfering with native biochemical processes, often used for labelling and tracking biomolecules.

Boron dipyrromethenes

(BODIPY). A class of fluorescent dyes with their high photostability and brightness, and used in various imaging applications.

Cyclic RGD peptides

Short peptides containing the amino acid sequence arginine–glycine–aspartic acid, which target integrins on cell membranes.

Dual-lock activation strategies

Methods that require two distinct triggers to activate a photosensitizer or drug, enhancing specificity and reducing off-target effects.

Enzyme-activatable PS

Photosensitizers that are activated by specific enzymes, allowing for targeted photodynamic therapy in areas wherein those enzymes are present.

Glutathione

(GSH). A tripeptide that acts as an antioxidant in cells, often used as a trigger for activating photosensitizers in anticancer therapy owing to its high levels in cancer cells.

Intramolecular charge transfer

(ICT). A process used in designing fluorescent probes and photosensitizers wherein a charge is transferred from an electron-rich donor moiety to an electron-poor acceptor moiety.

Near-infrared

(NIR). A region of the electromagnetic spectrum with wavelengths just beyond visible light and enhanced penetration in living tissues.

Photoinduced electron transfer

(PeT). A mechanism through which an electron is transferred between two chemical groups of photosensitizers and fluorophores, and used to quench or activate singlet oxygen generation or fluorescence emission, respectively.

Photosensitizers

(PS). Molecules that produce reactive oxygen species when exposed to light and used in photodynamic therapy to kill targeted cells.

Reactive oxygen species

(ROS). Chemically reactive molecules containing oxygen, which can cause cell damage and are used in photodynamic therapy to kill cancer cells or pathogens.

Singlet oxygen

A highly reactive form of oxygen generated by photosensitizers during photodynamic therapy, responsible for inducing cell death.

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Nestoros, E., Sharma, A., Kim, E. et al. Smart molecular designs and applications of activatable organic photosensitizers. Nat Rev Chem 9, 46–60 (2025). https://doi.org/10.1038/s41570-024-00662-7

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