Bioorthogonal Disassembly of Tetrazine Bearing Supramolecular Assemblies Inside Living Cells

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 pi-pi 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.

Automated summary

A bioorthogonal disassembly strategy was developed to prompt clearance of supramolecular assemblies within living cells. The enzyme-instructed self-assembly process led to the disruption of pi-pi stacking and induced disassembly of the assemblies, depriving them of potency and addressing their unintended retention and cellular toxicity. This strategy leverages biosafety in developing nanomaterials for drug delivery systems.