Nanomedicine constructed with plant-derived aromatic aldehydes treats low back pain by reversing the progression of lumbar facet joint osteoarthritis

• Aromatic aldehyde-based drug carriers have anti-inflammatory, antioxidant functions and pH responsiveness. • Microenvironment responsive and actively-targeting NDDSs enable accurate drug delivery and efficient release. • Regulation of macrophage polarization and cartilage injury repair achieve the treatment of LBP caused by FJOA. Lumbar facet joint osteoarthritis (FJOA) is a degenerative disease of the lumbar spine and the main cause of low back pain (LBP). Macrophage infiltration and chondrocyte damage are the main pathological features of FJOA, and the joint microenvironment has a low pH and high ROS levels. Herein, a pH/ROS dual-responsive drug carrier was developed with several aromatic aldehydes from different plant sources and used to fabricate a nanodrug delivery systems (NDDSs). Activated aromatic aldehydes not only have anti-inflammatory and antioxidant effects but also are pH-responsive, and carriers modified with 4-(hydroxymethyl) phenylboronic acid pinal ester (HPAP) are also ROS-responsive. In addition, RGD modification enhanced the active targeting ability of the NDDSs. In vitro, compared with unloaded Blank NPs constructed with cinnamaldehyde (CA), cumin aldehyde (CMA) and vanilla aldehyde (VA), Blank NPs constructed with syringaldehyde (SA) were found to have relatively greater anti-inflammatory effects. Further experiments revealed that multifunctional NPs (DEX/RGD-SA-HPAP-αCD NPs) generated by loading dexamethasone (DEX) onto SA-based carriers can strongly inhibit the macrophage-mediated inflammatory response through the NF-κB signalling pathway and promote the anabolism of chondrocytes to repair cartilage damage, thereby alleviating LBP caused by FJOA.