Endogenously Triggered DNAzyme‐Based Nanostructures for Gene‐Combined Therapy

Therapeutic DNAzyme, often activated by catalytic cofactors in its central catalytic domain, has been extensively explored for the treatment of diverse diseases, primarily through mechanisms involving free release, notably within gene therapy frameworks. Notwithstanding the substantial progress, challenges persist in precisely regulating the intracellular release of DNAzymes from nanostructures while ensuring their stability and integrity. Recent advancements in DNA nanotechnology have spurred the development of endogenous stimuli‐responsive functional DNA‐based nanosystems, enabling controlled release of DNAzyme by internal cues. This mini‐review examines recent innovations in the design and development of nanostructured platforms that enable the endogenously triggered release of DNAzymes, along with their catalytic cofactors, primarily for cleavage of a substrate such as messenger RNA (mRNA). These nanosystems hold promises for harnessing gene‐combined therapy by integrating multiple therapeutic modalities. Furthermore, the applications of these triggerable DNAzyme release‐based nanoplatforms in combinational therapies for cancer and other diseases are explored. Moreover, this contribution, pioneered by therapeutic DNAzyme, underscores the strategic integration of endogenously triggerable DNAzyme release in advancing therapeutic precision, particularly in gene‐combined therapy. Furthermore, the current research challenges and future perspectives in this rapidly evolving field are briefly highlighted and discussed.