Injectable GelMA microspheres encapsulating self-assembly apigetrin-loaded lipid nanoparticles for osteoarthritis via Nrf2–HO-1 pathway activation

Osteoarthritis (OA) is a progressive degenerative joint disorder characterized by articular cartilage degradation, persistent oxidative stress, and chronic inflammation. Targeting oxidative damage within the joint microenvironment represents a promising avenue for disease modification, offering potential to preserve cartilage integrity, alleviate inflammatory cascades, and ultimately delay structural progression. Lipid nanoparticles were prepared by thin-film hydration and extrusion, then embedded into GelMA microspheres via a microfluidic droplet platform with UV crosslinking to form a sustained-release system. Biocompatibility, ROS-scavenging, anti-inflammatory, and chondroprotective effects were evaluated in vitro and in vivo, while transcriptome sequencing was applied to elucidate system-induced molecular alterations. In vitro , Api-LNP@GMS markedly attenuated ROS accumulation and inflammatory responses in IL-1β-stimulated chondrocytes, as demonstrated by ROS fluorescence imaging, immunofluorescence, Western blotting, and qRT-PCR analyses. In vivo , intra-articular administration in anterior cruciate ligament transection (ACLT) rats effectively alleviated joint inflammation while preserving cartilage integrity and functional capacity. Moreover, transcriptome-wide RNA sequencing, integrated with pathway enrichment analysis and validated by molecular assays, revealed robust activation of the Nrf2–HO-1 antioxidant signaling axis. Api-LNP@GMS is a multifunctional antioxidant biomaterial platform that integrates a natural therapeutic with a sustained-release delivery system, offering a safe and effective strategy to reprogram the osteoarthritic microenvironment and mitigate disease progression. Download: Download high-res image (281KB) Download: Download full-size image