Unnatural Triggers Converted From Tetrazine‐Attached Sialic Acid for Activation of Optoacoustic Imaging‐Guided Cancer Theranostics

Constructing chemical groups on cell membranes through metabolic glycoengineering of unnatural sugars is an effective means to solve the issue of insufficient or even lack of targets in cancer theranostics. Herein, we address the limitations by developing a tetrazine precursor (SiaTz) based on a nonO-acetylated sialic acid scaffold and then utilizing it to create unnatural tetrazine triggers on the surface of cancer cells. SiaTz exhibits a good balance between the stability and reaction kinetics under physiological conditions and can be efficiently converted into corresponding tetrazine trigger through bypassing several size-limiting steps in metabolic glycoengineering process. We also prepare a proof-of-concept theranostic combination of a trans-cyclooctene derivative (CyTCO) and a thermal-sensitive drug 2,2'-azobis[2-(2-imidazolin-2-yl) propane]-dihydrochloride (AIPH) to verify the activation function of tetrazine triggers in theranostics of orthotopic and metastatic tumors. In the presence of tetrazine triggers, CyTCO can be activated via bio-orthogonal reaction to induce optoacoustic signal enhancement, enabling high-contrast diagnostic imaging and precise tumor localization to guide subsequent treatments. Tetrazine trigger-activated CyTCO displays high photo-to-heat conversion efficiency, which can cause an obvious increase in temperature under laser irradiation and then initiate AIPH decomposition to produce toxic radicals for combined therapy.