Quercetin loaded ZIF-8 coated human serum albumin nanoparticles relieve pulmonary fibrosis via NUAK1-YAP axis.

Quercetin (Que) exhibits considerable therapeutic potential against pulmonary fibrosis (PF), but its clinical translation is hindered by poor aqueous solubility and low bioavailability. To address these limitations, we developed a highly biocompatible nanoplatform by encapsulating Que within ZIF-8 nanoparticles surface-modified with human serum albumin (HSA). The resulting Que@ZIF-8/HSA nanoparticles were synthesized via co-precipitation and subsequent surface modification. Comprehensive in vitro biocompatibility was verified across multiple lung cell lines. The therapeutic mechanism was investigated by analyzing M2 macrophage polarization, oxidative stress, and fibroblast activation in a macrophage-fibroblast co-culture system. The in vivo efficacy of the nanoplatform was subsequently validated in a bleomycin-induced PF mouse model using micro-CT, pulmonary function testing, and histopathological analysis. The Que@ZIF-8/HSA nanoparticles exhibited excellent colloidal stability and sustained drug release profiles with negligible systemic toxicity. Mechanistically, the nanoplatform significantly attenuated M2 macrophage polarization and mitigated oxidative damage. Notably, Que@ZIF-8/HSA-treated macrophages were found to restrict YAP nuclear translocation via NUAK1 inhibition in fibroblasts, thereby preventing the fibroblast-to-myofibroblast transition. These cellular changes translated into reduced collagen deposition and markedly improved respiratory function in vivo. Thus, Que@ZIF-8/HSA effectively disrupts the macrophage-fibroblast crosstalk through the NUAK1/YAP signaling axis, offering a potent, biocompatible microenvironment-responsive nanoplatform for Que delivery and the clinical management of PF.