Bioorthogonal Disassembly of Tetrazine Bearing Supramolecular Assemblies Inside Living Cells

• Published in: Small (Weinheim an der Bergstrasse, Germany) Vol. 18; no. 2; pp. e2104772 - n/a
• Main Authors: Song, Jialei, Wu, Chengling, Zhao, Yan, Yang, Min, Yao, Qingxin, Gao, Yuan
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.01.2022
• Subjects: Assemblies; bioorthogonal reactions; Cells (biology); Dismantling; Drug Delivery Systems; enzyme‐instructed self‐assembly; Hydrogels; Nanofibers; Nanomaterials; Nanostructures; Nanotechnology; self‐immolative supramolecular nanomaterials; Toxicity; toxicity; nanomaterials; bioorthogonal reactions; enzyme-instructed self-assembly; self-immolative supramolecular nanomaterials
• ISSN: 1613-6810; 1613-6829
• DOI: 10.1002/smll.202104772

Supramolecular assemblies are an emerging class of nanomaterials for drug delivery systems (DDS), while their unintended retention in the biological milieu remains largely unsolved. To realize the prompt clearance of supramolecular assemblies, the bioorthogonal reaction to disassemble and clear the supramolecular assemblies within living cells is investigated here. A series of tetrazine‐capped assembly precursors which can self‐assemble into nanofibers and hydrogels upon enzymatic dephosphorylation are designed. Such an enzyme‐instructed supramolecular assembly process can perform intracellularly. The time‐dependent accumulation of assemblies elicits oxidative stress and induces cellular toxicity. Tetrazine‐bearing assemblies react with trans‐cyclooctene derivatives, which lead to the disruption of π–π stacking and induce disassembly. In this way, the intracellular self‐assemblies disassemble and are deprived of potency. This bioorthogonal disassembly strategy leverages the biosafety aspect in developing nanomaterials for DDSs. Besides the bioorthogonal labeling and prodrugs activation, the reaction between tetrazine and trans‐cyclooctene can disrupt π–π stacking and induce the disassembly of a series of enzyme‐instructed supramolecular assemblies in vitro and inside living cells. Such a bioorthogonal disassembly strategy actively removes assemblies in the biological milieu to alleviate nano‐toxicities, which may be applicable for treating aberrant protein assemblies.