Programmable DNAzyme nanocatalysts for tumor immunometabolic modulation.

内容摘要

Programmable RNA-cleaving DNAzymes (RCDs) represent a unique class of catalytic nucleic acids that couple molecular recognition with enzyme-like activity. While DNAzymes have traditionally been explored for targeted gene regulation, recent advances in nanotechnology have repositioned them as programmable biosensing modules with stimuli-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 stimuli-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. RNA切割型DNAzyme是一类兼具分子识别能力和酶样催化活性的功能核酸分子，在靶向基因调控、生物传感和肿瘤治疗中具有重要应用潜力。近年来，随着纳米技术的发展，DNAzyme可与金属氧化物、DNA框架结构、金属有机框架等纳米平台集成，形成具有递送保护、金属辅因子供给和肿瘤微环境响应能力的程序化纳米催化体系。这类体系能够响应pH、氧化还原稳态、金属离子和microRNA等内源性信号，并将其转化为特异性RNA催化切割输出。本文系统综述了DNAzyme催化机制、序列与化学工程策略、纳米平台构建方式及其在肿瘤免疫代谢调控中的应用。重点讨论了DNAzyme纳米催化剂如何通过调节糖酵解、氧化还原稳态、线粒体功能、营养竞争及cGAS-STING相关免疫信号，缓解肿瘤免疫抑制并促进抗肿瘤免疫激活。最后，本文总结了该领域在体内递送、辅因子供给、催化特异性、生物安全性和标准化评价方面面临的转化挑战，并展望其作为生物传感引导的肿瘤免疫代谢干预平台的发展前景。.