A Hydrogen‐Bonded Organic Framework‐Based DNase I Delivery System for Targeted Suppression of the cGAS‐STING Pathway in Acute Lung Injury

ABSTRACT In sepsis‐induced acute lung injury (ALI), mitochondrial DNA (mtDNA) released from damaged lung cells is recognized by the cytosolic DNA sensor cyclic GMP‐AMP synthase (cGAS), leading to aberrant activation of the stimulator of interferon genes (STING) pathway. This signaling cascade amplifies inflammation and oxidative stress, ultimately resulting in severe pulmonary dysfunction and high mortality. Here, we present a hydrogen‐bonded organic framework (HOF‐101)‐based delivery system for DNase I that enables enzymatic clearance of cytosolic DNA and targeted suppression of the cGAS‐STING pathway in ALI. Following efficient pulmonary delivery and macrophage internalization, this DNase I@HOF‐101 platform effectively clears intracellular mtDNA, thereby attenuating inflammatory responses and alleviating acute lung injury. Moreover, the system exhibits desirable biocompatibility, minimal cytotoxicity, and enhanced enzymatic stability, highlighting its potential as a nanotherapeutic strategy for cGAS‐STING‐mediated inflammatory diseases.