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

Abstract 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.