One-pot synthesis of storage-stable, tumor-specific cascade DNA nanobioreactors for ultrasound-promoted synergistic therapy

The application of therapeutic gas to treat tumors is an emerging "green" paradigm. However, the design of high-performace cascade nanobioreactors to convert gas donor into gas molecule in tumor microenvironment still remains challenging. Herein, hierarchical porous DNA nanoflowers (DNF) with programmable sequences are synthesized via one-pot rolling circle amplification, during which glucose oxidase (GOx) and L-arginine (L-Arg) are steadily associated with the polymeric DNA strands and magnesium pyrophosphate crystals. Through encoding of the corresponding aptamer, the as-synthesized storage-stable nanobioreactors L-Arg/GOx@DNF can specifically accumulate into HER2-overexpressed tumors to initialize high-performance cascade catalysis. For the first catalytic stage, GOx in L-Arg/GOx@DNF consumes the energy source of glucose intratumorally to starve tumor cells. Meanwhile, vast toxic H2O2 is generated to aggravate the mitochondrial dysfunction and G2/M phase arrest of vulnerable starved cells. Subsequently, H2O2 further triggers the second stage of catalytic reaction by oxidization of L-Arg into nitric oxide (NO) to synergize with the starvation effect of glucose consumption and chemodynamic effect of H2O2 elevation. Importantly, the external ultrasound irradiation can decompose H2O2 into highly reactive oxygenated species for enhanced oxidation of L-Arg, resulting in the augmented starvation/chemodynamic/gas therapy to synergistically inhibit tumor growth.