Protein-Controlled Photochemical Redirection Enables Proximity-Activated Red-Light Photocatalytic Pharmacology
4 affiliations
- 1Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences , , 345 Lingling Road , ,
- 2ShanghaiTech University , 100 Haike Road , ,
- 3Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, University of Chinese Academy of Sciences , , ,
- 4School of Chemistry and Material Sciences, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences , 1 Sub-lane Xiangshan , ,
Abstract
Red-light photocatalysis offers opportunities for noninvasive molecular regulation but is challenged by competing pathways that generate cytotoxic reactive oxygen species. Here, we report a protein-controlled photochemical redirection strategy for proximity-activated red-light photocatalytic pharmacology through bioorthogonal deboronative hydroxylation. By integrating a silicon rhodamine (SiR) photocatalyst with a HaloTag scaffold, we establish a protein–photocatalyst hybrid that stabilizes and confines the photoactive open zwitterionic SiR state. Mechanistic studies associate a higher open-state population with preferential Type I photochemical reactivity, supporting superoxide radical anion generation and downstream hydrogen peroxide formation while strongly suppressing singlet oxygen production (ΦΔ = 0.0027). This enables efficient deboronative hydroxylation with yields exceeding 99% and high cellular compatibility. The genetically targetable platform enables proximity-activated pharmacological regulation in living cells. Nuclear-localized release of an HDAC inhibitor increased histone H3 lysine 9 acetylation (H3K9ac) to 2.9 times the control level, compared with 1.9 times the control level following nonlocalized activation under identical conditions, demonstrating that pharmacological outcomes depend on the subcellular site of photocatalytic activation. Photocatalytic activity was also retained through a 1.5 mm tissue barrier under attenuated illumination. These findings establish protein-mediated stabilization and confinement of a photoactive chromophore as a strategy for controlling red-light photochemical reactivity and enabling proximity-activated photocatalytic pharmacology in living systems.
Related
- Polymer Brush-Mediated Surface-Initiated Polycondensation Enables sp2C-COF Thin Films with Controlled Crystallinity and High Photocatalytic Performance
- Electrodeposited Pd/TiO2 Nanotube Arrays with Size-Controlled Pd for High-Performance UV and Visible-Light Photocatalytic Water Remediation
- Zinc Redox Catalysis in the Photochemical Borylation of Fluorocarbons
- Direct photochemical activation of aliphatic carboxylic acids toward phosphinylation via polarity-reversed Arbuzov process
- Photochemical deracemization of α-chiral carboxamides mediated by inter- and intramolecular hydrogen bonding
BibTeX
@article{he2026proteincontrolled,
title = {{Protein-Controlled Photochemical Redirection Enables Proximity-Activated Red-Light Photocatalytic Pharmacology}},
author = {Ru He and Qihang Zhao and Zikang Chen and Xiuyu Wang and Qiaoling Che and Kaixing Zeng and Yi Zeng and Yixin Zhang and Yiyun Chen},
journal = {ACS Central Science},
year = {2026},
month = nov,
doi = {10.1021/acscentsci.6c01125},
url = {https://pubs.acs.org/acscii/article/doi/10.1021/acscentsci.6c01125/5463487/Protein-Controlled-Photochemical-Redirection},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Protein-Controlled Photochemical Redirection Enables Proximity-Activated Red-Light Photocatalytic Pharmacology
AU - Ru He
AU - Qihang Zhao
AU - Zikang Chen
AU - Xiuyu Wang
AU - Qiaoling Che
AU - Kaixing Zeng
AU - Yi Zeng
AU - Yixin Zhang
AU - Yiyun Chen
PY - 2026
DA - 2026/11/04
JO - ACS Central Science
DO - 10.1021/acscentsci.6c01125
UR - https://pubs.acs.org/acscii/article/doi/10.1021/acscentsci.6c01125/5463487/Protein-Controlled-Photochemical-Redirection
AB - Red-light photocatalysis offers opportunities for noninvasive molecular regulation but is challenged by competing pathways that generate cytotoxic reactive oxygen species. Here, we report a protein-controlled photochemical redirection strategy for proximity-activated red-light photocatalytic pharmacology through bioorthogonal deboronative hydroxylation. By integrating a silicon rhodamine (SiR) photocatalyst with a HaloTag scaffold, we establish a protein–photocatalyst hybrid that stabilizes and confines the photoactive open zwitterionic SiR state. Mechanistic studies associate a higher open-state population with preferential Type I photochemical reactivity, supporting superoxide radical anion generation and downstream hydrogen peroxide formation while strongly suppressing singlet oxygen production (ΦΔ = 0.0027). This enables efficient deboronative hydroxylation with yields exceeding 99% and high cellular compatibility. The genetically targetable platform enables proximity-activated pharmacological regulation in living cells. Nuclear-localized release of an HDAC inhibitor increased histone H3 lysine 9 acetylation (H3K9ac) to 2.9 times the control level, compared with 1.9 times the control level following nonlocalized activation under identical conditions, demonstrating that pharmacological outcomes depend on the subcellular site of photocatalytic activation. Photocatalytic activity was also retained through a 1.5 mm tissue barrier under attenuated illumination. These findings establish protein-mediated stabilization and confinement of a photoactive chromophore as a strategy for controlling red-light photochemical reactivity and enabling proximity-activated photocatalytic pharmacology in living systems.
SN - 2374-7943
SN - 2374-7951
ER -