Low-Solvent Mechanochemical MOF Carrier Nanoarchitectonics for Targeted Quercetin Delivery for Dual-Mode ROS and Anti-inflammation Protection against LPS-Induced Acute Lung Injury

Nowadays, inhalable administration of nanomedicines is an appealing concept for acute lung injury (ALI). For ALI nanomedicine, it is appealing to achieve targeted delivery and on-demand release in the ALI microenvironment, which is acidic, rich in reactive oxygen species (ROS), and with elevated inflammatory mediator levels. Notably, customized metal-organic frameworks (MOFs) could fulfill these requirements and thus are promising nanocarriers for ALI medicine delivery, but MOFs formulated often suffer from unreacted residues with hazardous risk. Herein, we report a low-solvent mechanochemical synthesis method to formulate cerium-doped zeolitic imidazolate frameworks (Ce-ZIFs) stabilized by Pluronic F127 as drug delivery nanocarriers to load quercetin for targeted preventive ALI therapy. The nanoplatform exhibits robust structural integrity, high drug loading capacity, excellent biocompatibility, and pH-responsive release of quercetin under acidic conditions, mimicking the inflamed lung microenvironment. Importantly, the nanoplatform ameliorates pro-inflammatory mediators (TNF-α, IL-6), inhibits pulmonary edema, and attenuates alveolar injury in an LPS-induced ALI mouse model. Notably, Ce/ZIF promotes the Ce+3/Ce+4 redox process to generate catalase-like activity for catalytic reactive oxygen species (ROS) scavenging and sustainable antioxidant properties. Transcriptome sequencing and biological validation also revealed that the nanoplatform showed its remarkable ability to counteract LPS-induced oxidative damage and inflammatory responses by suppressing Th1 cell polarization. This work demonstrates a Ce/ZIF platform formulated using a scalable, low-solvent mechanochemical synthesis method, presenting a biocompatible MOF platform with significant promise for targeted pulmonary delivery with protective potential against LPS-induced acute lung injury.