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Abstract Photodynamic therapy (PDT) is currently limited by the inability of photosensitizers (PSs) to enter cancer cells and generate sufficient reactive oxygen species. Utilizing phosphorescent triplet states of novel PSs to generate singlet oxygen offers exciting possibilities for PDT. Here, we report phosphorescent octahedral molybdenum (Mo)‐based nanoclusters (NC) with tunable toxicity for PDT of cancer cells without use of rare or toxic elements. Upon irradiation with blue light, these molecules are excited to their singlet state and then undergo intersystem crossing to their triplet state. These NCs display surprising tunability between their cellular cytotoxicity and phototoxicity by modulating the apical halide ligand with a series of short chain fatty acids from trifluoroacetate to heptafluorobutyrate. The NCs are effective in PDT against breast, skin, pancreas, and colon cancer cells as well as their highly metastatic derivatives, demonstrating the robustness of these NCs in treating a wide variety of aggressive cancer cells. Furthermore, these NCs are internalized by cancer cells, remain in the lysosome, and can be modulated by the apical ligand to produce singlet oxygen. Thus, (Mo)‐based nanoclusters are an excellent platform for optimizing PSs. Our results highlight the profound impact of molecular nanocluster chemistry in PDT applications.
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This content will become publicly available on May 29, 2026
dTAT1: An Unnatural Nucleoside Exhibiting Low Photocytotoxicity for Genetic Code Expansion
Synthetic biology aims to expand the genetic code by increasing cellular information storage and retrieval. A recent advance is the dTAT1-dNaM unnatural base pair, which is more photo- and thermostable than dTPT3-dNaM while maintaining high efficiency and fidelity in vitro and in vivo. However, the photophysics and cytotoxicity behavior of dTAT1 under UV light have not been investigated. We demonstrate that dTAT1 populates the triplet state upon 390 nm excitation but exhibits minimal cytotoxicity in cells. Analysis of reactive oxygen species indicates that dTAT1 produces a low singlet oxygen quantum yield of 17% while it generates superoxide, a less harmful reactive oxygen species. Its triplet lifetime is 2.7 times shorter than that of dTPT3, contributing to its lower photocytotoxicity. These findings highlight the potential of dTAT1 for safe genetic code expansion and therapeutic applications, providing valuable insights for designing next-generation unnatural nucleosides with minimal impact on cellular health.
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- Award ID(s):
- 2246805
- PAR ID:
- 10595976
- Publisher / Repository:
- ACS
- Date Published:
- Journal Name:
- The Journal of Physical Chemistry Letters
- Volume:
- 16
- Issue:
- 21
- ISSN:
- 1948-7185
- Page Range / eLocation ID:
- 5390 to 5397
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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