AIEgen-mediated integration of plain DNA and hydrophobic compounds enabling three-in-one nanosystems for carrier-free delivery.

DNA has been serving as a powerful and programmable vector for drug delivery, yet facile strategies for the direct loading of hydrophobic payloads onto DNA vehicles are still lacking but highly demanded. In this work, we report an AIEgen-mediated approach for the integration of plain DNA and hydrophobic molecules into nanospheres upon heating treatment. The broad applicability of this strategy is established by loading nine different hydrophobic molecules with high loading capacity, including six therapeutic drugs and three fluorescent dyes. Owing to the compact configuration, the nano-systems show superior stability under physiologically relevant conditions while the AIEgen displays significantly enhanced fluorescent signal and reactive oxygen species-generating ability upon light irradiation. In vitro studies validate the successful cellular delivery of the nanosystems, as evidenced by effective cell staining with fluorescent dyes and synergistic cytotoxicity from the combined action of loaded drugs and AIEgen-mediated photodynamic therapy (PDT). Finally, by using sorafenib and an antisense oligonucleotide (ASO), we demonstrate the synergistic antitumor efficacy of the nanodrug in vitro and in vivo: while ASO prolongs intracellular drug retention by down-regulating the efflux factor P-glycoprotein, sorafenib can amplify the PDT efficacy of the AIEgen by depleting glutathione and glutathione peroxidase 4. Therefore, our work establishes an effective AIEgen-mediated and heat-promoted strategy for creating multifunctional nanosystems, which may find widespread application in carrier-free delivery for disease theranostics.