Propelled Transnuclear Gene Transport Achieved through Intracellularly Redox-Responsive and Acidity-Accelerative Decomposition of Supramolecular Florescence-Quenchable Vectors

Intracellularly biotriggered decomposition of gene vectors is generally thought to benefit transfection. However, the bioresponsiveness is far from satisfactory, and the exact role of biodecomposition in the transfection process remains unclear to date. To overcome the challenges, highly rapid bioresponse of vectors has to be achieved so as to greatly amplify the intracellular deviation compared with the noncontrolled pattern. To this end, a supramolecular polyrotaxane has been elaborately designed by integrating reversible dynamics of supramolecular assembly and chemically labile bonds, in order to effectively propel intracellular decomposition. Inside tumor cells, the redox-responsive bulk dissociation of the supramolecular vector readily took place and was further accelerated by the lysosomal-acidity-triggered terminal decomposition. Both the in vitro and in vivo experiments have demonstrated that this supramolecule could mediate considerably more rapid gene accumulation in nuclei than the nonresponsive controls including PEI25K, the gold standard of nonviral vectors. Along with the structural decomposition, the supramolecule simultaneously underwent the transition of fluorescence quenching, favoring the evaluation over the bioresponsiveness inside cells. Based on the resulting data, it is suggested that the biotriggered volume expansion of supramolecule/DNA complexes may be the major factor accounting for that dramatically accelerated transnuclear gene transport during cellular mitosis, thus affecting the transfection. This study offers an understanding of the intracellular gene transport from a new viewpoint.