Issue 42, 2023

Acyl-caged rhodamines: photo-controlled and self-calibrated generation of acetyl radicals for neural function recovery in early AD mice

Abstract

The biological function of radicals is a broad continuum from signaling to killing. Yet, biomedical exploitation of radicals is largely restricted to the theme of healing-by-killing. To explore their potential in healing-by-signaling, robust radical generation methods are warranted. Acyl radicals are endogenous, exhibit facile chemistry and elicit matrix-dependent biological outcomes. Their implications in health and disease remain untapped, primarily due to the lack of a robust generation method with spatiotemporal specificity. Fusing the Norrish chemistry into the xanthene scaffold, we developed a novel general and modular molecular design strategy for photo-triggered generation of acyl radicals, i.e., acyl-caged rhodamine (ACR). A notable feature of ACR is the simultaneous release of a fluorescent probe for cell redox homeostasis allowing real-time monitoring of the biological outcome of acyl radicals. With a donor of the endogenous acetyl radical (ACR575a), we showcased its capability in precise and continuous modulation of the cell redox homeostasis from signaling to stress, and induction of a local oxidative burst to promote differentiation of neural stem cells (NSCs). Upon intracerebral-injection of ACR575a and subsequent fiber-optical activation, early AD mice exhibited enhanced differentiation of NSCs toward neurons, reduced formation of Aβ plaques, and significantly improved cognitive abilities, including learning and memory.

Graphical abstract: Acyl-caged rhodamines: photo-controlled and self-calibrated generation of acetyl radicals for neural function recovery in early AD mice

Supplementary files

Article information

Article type
Edge Article
Submitted
14 6 2023
Accepted
13 9 2023
First published
14 9 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2023,14, 11689-11698

Acyl-caged rhodamines: photo-controlled and self-calibrated generation of acetyl radicals for neural function recovery in early AD mice

X. Luo, Z. Zhang, J. Wang, X. Wang, Y. Zhang, J. Chen, G. Ge, W. Yang, X. Qian, Y. Tian and Y. Yang, Chem. Sci., 2023, 14, 11689 DOI: 10.1039/D3SC03035K

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