LAUSR

Mimicking nature's ability to orchestrate molecular self-assembly in living cells is important yet challenging. Molecular self-assembly has found wide applications in cellular activity control, drug delivery, biomarker imaging, etc. Nonetheless, exam-ples of suborganelle-confined supramolecular self-assembly are quite rare and research in this area remains challenging. Herein, we have presented a new strategy to program supramolecular self-assembly specifically in mitochondria by leverag-ing on a unique enzyme SIRT5. SIRT5 is a mitochondria-localized enzyme belonging to a family of NAD+-dependent histone deacetylases. Accumulating studies suggest that SIRT5 is involved in regulating diverse biological processes, such as reactive oxygen defense, fatty acid metabolism and apoptosis. In this study, we designed a novel class of succinylated peptide precur-sors that can be transformed into self-assembling building blocks through SIRT5 catalysis, leading to the formation of supra-molecular nanofibers in vitro and in living cells. The increased hydrophobicity arising from self-assembly remarkably en-hanced the fluorescence of nitrobenzoxadiazole (NBD) in the nanofibers. With this approach, we have enabled activity-based imaging of SIRT5 in living cells for the first time. Moreover, SIRT5-mediated peptide self-assembly was found to depolarize mitochondria membrane potential and promote ROS formation. Co-incubation of the peptide with three different chemo-therapeutic agents significantly boosted the anticancer activities of these drugs. Our work has thus illustrated a new way of mitochondria-confined peptide self-assembly for SIRT5 imaging and potential anticancer treatment.