A bioluminescent probe, BLGLN, comprising BL568 and ASCT2-uptaken AA201, enables real-time monitoring and evaluation of ASCT2-mediated glutamine uptake rates in living tumors via Staudinger ligation, aiding tumor metabolism studies and targeted therapeutics. Abstract Glutamine addiction, as a hallmark of tumor metabolism, drives malignant progression via proliferation, survival, and metastasis. Alanine-serine-cysteine transporter 2 (ASCT2), the primary glutamine transporter, is overexpressed in tumors to meet metabolic demands, making it a promising therapeutic target. Accurately monitoring ASCT2-mediated glutamine uptake is essential for investigating tumor metabolism and developing ASCT2-targeted therapeutics. However, current methods lack specificity, require laborious sample processing, and do not support real-time measurements in living systems. To overcome these issues, BLGLN is designed, an innovative bioluminescent reporter system exploiting Staudinger ligation. BLGLN comprises two components: 1) BL568, a caged D-luciferin derivative protected with 2-diphenylphosphinobenzoic acid, and 2) AA201, an azide-modified glutamine mimetic taken up by ASCT2. Once inside, AA201 undergoes Staudinger ligation with membrane-permeable BL568, releasing D-luciferin that is converted by luciferase into a bioluminescent signal, allowing real-time tracking of ASCT2-dependent glutamine uptake in tumors. BLGLN provides simplified synthesis, eliminates complex sample preparation, and enables real-time tracking and evaluation of glutamine uptake rate in living tumors.

Proteolysis-targeting chimeras (PROTACs) have transformed therapeutic interventions by hijacking the ubiquitin–proteasome system. However, their broad application is hindered by inadequate cellular permeability and undesired off-tissue effects. Here, we introduce a modular strategy for the in situ synthesis of PROTACs through pathologically activated bioorthogonal catalysis (ABC-PROTAC), enabling targeted protein degradation specifically in cancer cells. This platform integrates biocompatible, glutathione-activated Click-T-Cu(II) complexes with azido- and acetylene-derived, fragmented PROTAC precursors. These components are encapsulated within AS1411 aptamer-conjugated liposomes to enhance cellular uptake and systemic delivery. Once internalized by nucleolin-overexpressing cancer cells, the Click-T-Cu(II) complexes are activated to catalyze the intracellular assembly of functional PROTACs via click chemistry. This delivery paradigm facilitates efficient degradation of oncoproteins both in vitro and in vivo, resulting in robust antitumor activity with favorable biocompatibility and high selectivity. The modularity of the ABC-PROTAC strategy is demonstrated by utilizing diverse warheads, including small molecules and DNA motifs, to degrade BRD4, PARP1, and NF-κB. Together, this strategy establishes a precise method for targeted protein degradation while minimizing the systemic toxicity associated with conventional PROTACs.

Triggerable and fluorogenic bioorthogonal reactions are a powerful tool for a multitude of biological and materials science applications. The concepts of light-activated tetrazines and fluorogenic…

Carolyn Bertozzi and colleagues laid out a way to make paradigm-shifting "click-chemistry" compatible with living cells, opening up a window into living organisms.

In vivo identification and characterization of atherosclerosis is a promising approach for the development of novel therapies and personalized treatments. Among the methods for this in vivo identifica...

Engineered aminoacyl-tRNA synthetase (aaRS) mutants have been developed that facilitate ultrafast bioorthogonal noncanonical amino acid tagging (BONCAT) of newly synthesized proteins in diverse bacteria, including ESKAPE pathogens. The substrate polyspecificity of the aaRS mutants enables pulse-chase BONCAT and differential tagging of temporally distinct nascent proteomes in cells.

Engineered aminoacyl-tRNA synthetase (aaRS) mutants have been developed that facilitate ultrafast bioorthogonal noncanonical amino acid tagging (BONCAT) of newly synthesized proteins in diverse bacteria, including ESKAPE pathogens. The substrate polyspecificity of the aaRS mutants enables pulse-chase BONCAT and differential tagging of temporally distinct nascent proteomes in cells.

Communications Chemistry, Published online: 03 October 2025; doi:10.1038/s42004-025-01685-xGangliosides play crucial roles in the nervous system, with aberrant metabolism linked to diseases like cancer and neurodegeneration, but tools to visualize and detect gangliosides remain limited and non-specific. Here, the authors introduce MM-JH-2, a dual fluorescent and Raman-active probe, enabling specific ganglioside labeling and differentiation between cells that differ in ganglioside biosynthetic flux.

At the intersection of chemical biology, plant imaging, and contemporary art, this review introduces the concept of chembioart. By tracing how chemical reporters illuminate plant biomolecules in vivo...

Stone, S. E., Glenn, W. S., Hamblin, G. D. & Tirrell, D. A. Cell-selective proteomics for biological discovery. Curr. Opin. Chem. Biol. 36, 50–57 (2017). Van Bergen, W., Heck, A. J. R. & Baggelaar, M. P. Recent advancements in mass...

Pro-apoptotic receptor activators (PARAs), including second-generation agonist antibodies and ligands targeting the TNF receptor superfamily such as T…