DNA addition polymerization with logic operation for controllable self-assembly of three-dimensional nanovehicles and combinatorial cancer therapy

Abstract

Nucleic acid, as a design medium, has become one of the most promising biopolymers to perform the dynamic functions, such as catalytic hybridization, target triggered self-assembly and DNA computing in the applications of biosensing, bioimaging and biomedicine. Herein, a DNA addition polymerization (DAP) reaction is proposed to guide the DNA self-assembly towards the construction of size-controlled DNA nanospheres (DNSs). Analogous to chemical step-growth addition polymerization, our proposed DAP reaction is carried out using DNA dimer and DNA hairpin as monomers, in which the initiator acts as both the stimulus and catalyst and N-arm DNA junctions as the structural units, resulting in the formation of three-dimensional DNSs without the generation of by-product. Notably, the designed DAP paradigm is consistent with the molecular logic operation consisted of cascaded AND gates with a feedback mechanism. Further, a versatile nano-drug delivery system is successfully constructed via functionalization the DNSs with chemo-drug (doxorubicin, Dox) and two different siRNAs (anaplastic lymphoma kinase-specific siRNA (ALK-siRNA) and survivin siRNA (Sur-siRNA)) simultaneously. The multifunctional DNSs with good stability and biocompatibility in vitro and in vivo demonstrate an excellent performance in gene-chemo combination therapy of anaplastic large cell lymphoma (ALCL). Overall, the DAP strategy provides a simple yet practical route to build multifunctional DNA nanomaterials, which sheds new light on the development of DNA nanotechnology and cancer therapy.