Abstract: Programmable RNA-cleaving DNAzymes (RCDs) represent a unique class of catalytic nucleic acids that couple molecular recognition with enzyme-like activity. While DNAzymes have been traditionally explored for targeted gene regulation, recent advances in nanotechnology have repositioned them as programmable biosensing modules with stimulus-responsive therapeutic potential. When integrated into metal-oxide scaffolds, DNA-framework architectures or metal-organic frameworks, DNAzymes form hybrid platforms that create confined catalytic microenvironments, provide enriched cofactor availability, and facilitate microenvironment-responsive activation. These engineered systems can function as nanoscale biosensing modules that respond to pH, redox gradients, metal ions, or microRNA signatures and convert these biological cues into catalytic outputs. Beyond enhancing analytical performance, such platforms may also reshape tumor immunometabolism. Through the selective cleavage of metabolic or immune-regulatory transcripts, DNAzyme nanocatalysts can directly reprogram glycolysis, redox balance, oxygen tension and mitochondrial activity and these metabolic changes in turn alleviate immunosuppression and promote innate and adaptive immune activation. This review outlines the mechanistic foundations of DNAzyme catalysis, summarizes recent nanoengineering strategies that endow DNAzymes with programmable sensing and stimulus-responsive functions, and discusses how these systems bridge biosensing and catalytic immunometabolic functions. We conclude with perspectives on translational challenges and opportunities, endorsing programmable DNAzyme nanocatalysts as emerging preclinical platforms for biosensing-guided immunometabolic intervention.

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