Enzyme‐Responsive Nanoparachute for Targeted miRNA Delivery: A Protective Strategy Against Acute Liver and Kidney Injury

Abstract MicroRNA (miRNA)‐based therapy holds significant potential; however, its structural limitations pose a challenge to the full exploitation of its biomedical functionality. Framework nucleic acids are promising owing to their transportability, biocompatibility, and functional editability. MiRNA‐125 is embedded into a nucleic acid framework to create an enzyme‐responsive nanoparachute (NP), enhancing the miRNA loading capacity while preserving the attributes of small‐scale framework nucleic acids and circumventing the uncertainty related to RNA exposure in conventional loading methods. An enzyme‐sensitive sequence is designed in NP as a bioswitchable apparatus for cargo miRNAs release. NP is compared with conventional delivery modes and delivery vehicles, confirming its excellent transportability and sustained release properties. Moreover, NP confers good enzyme and serum resistance to the cargo miRNAs. Simultaneously, it can easily deliver miRNA‐125 to liver and kidney lesions owing to its passive targeting properties. This allows for Keap1/Nrf2 pathway regulation and p53 protein targeting in the affected tissues. Additionally, NP negatively regulates the expression of Bax and Caspase‐3. These combined actions help to inhibit oxidation, prevent cell cycle arrest, and reduce the apoptosis of liver and kidney cells. Consequently, this strategy offers a potential treatment for acute liver and kidney injury.