Intelligent responsive DNA nanoflowers for combined chemo-gene-photothermal therapy of cancer

Although DNAzymes have been extensively explored for cancer treatment, their clinical application is limited due to the lack of intrinsic cofactors and unsatisfactory monotherapy effects. Herein, DNA nanoflowers (DNFs) were synthesized via rolling circle amplification (RCA), which were encoded with DNAzyme sequences and enriched with magnesium. Subsequently, by loading doxorubicin (DOX), coating with metal-polyphenol networks (MPN), and functionalizing with hyaluronic acid (HA), a multimodal therapeutic nanoplatform (DNF@DOX@MPN@HA, FDMH) was constructed. The FDMH nanoparticles (NPs) efficiently entered target cells through HA-mediated CD44 receptor recognition. Under the irradiation of an 808 nm laser, the MPN coating converted light energy into heat energy to achieve photothermal therapy (PTT). In the acidic intracellular environment, the flower-like structure of DNF disintegrated into linear DNA strands, simultaneously releasing Mg^2 + and DOX. The released DOX translocated to the nucleus of the cell to exert chemotherapeutic effects, while the Mg²⁺ acted as a cofactor to activate the DNAzyme for catalytic cleavage of survivin mRNA for gene therapy (GT). Experimental results demonstrated that FDMH could be efficiently internalized by cells and exhibited potent antitumor efficacy. This work presents a promising strategy for combination cancer therapy.