Targeted delivery of hesperetin to cartilage attenuates osteoarthritis by bimodal imaging with Gd2(CO3)3@PDA nanoparticles via TLR-2/NF-κB/Akt signaling.

The progressive degeneration of cartilage marks the advancement of osteoarthritis (OA), which requires specific targeted treatment for effective cartilage repair. However, there is still no efficient cartilage delivery system or novel magnetic resonance (MR) contrast agent (CA). Herein, we report the synthesis of a novel class of MR CA, Gd₂(CO₃)₃-based nanoparticles (NPs), from a simpler and "greener" approach than previous ones. After the coating of polydopamine (PDA) onto the Gd₂(CO₃)₃ core, we further anchored a cartilage-targeting peptide and loaded hesperetin (Hes) into NPs (Hes-Gd₂(CO₃)₃@PDA-PEG-DWpeptide, HGdPDW), showing excellent cartilage affinity and MR suitability. Additionally, the synthesized HGdPDW exerted significant protective effects against IL-1β stimulation, as shown by the decreased apoptosis and inflammation and increased maturation of chondrocytes in vitro. More importantly, RNA-seq analyses showed the significant reduction of TLR-2 in IL-1β-treated chondrocytes, and this reduction was followed by the inactivation of NF-κB/Akt signaling, leading to the protective effect of HGdPDW. By the establishment of anterior cruciate ligament transection (ACLT) OA mice, the bimodal MRI/IVIS imaging demonstrated the effective cartilage-binding ability of HGdPDW in OA knees with low cytotoxicity, which alleviated the gradual degeneration of articular cartilage in vivo by inhibiting TLR-2 in chondrocytes. Taken together, these results suggest that HGdPDW could target cartilage effectively, thereby protecting chondrocytes from apoptosis and inflammation via TLR-2/NF-κB/Akt signaling. We hope this new class of MRI CA could be applied in not only other fields using MRI technology but also the treatment of general cartilage-related diseases; this application will undoubtedly extend the treatment of OA clinically.