Cascade-Targeting Hydrogel Microspheres with Biomimetic Nanoparticles Enable Multifaceted Anti-Inflammatory and Antioxidant Defense for Osteoarthritis Management

Abstract

Osteoarthritis (OA), an age-related chronic inflammatory disorder, is characterized by synovitis and progressive cartilage degradation. The pathological progression of OA is closely associated with reactive oxygen species (ROS) overproduction, which drives macrophage polarized to M1 phenotype and cartilage matrix catabolism. Therefore, targeted elimination of intra-articular ROS and modulation of macrophage polarization represent promising strategies to attenuate OA. In this study, macrophage membranes (MM) were extracted using membrane extrusion techniques, followed by encapsulation of selenium nanoparticles (SeNPs), thus constructing biomimetic nanoparticles (SeNPs@MM). Hyaluronic acid (HA), methacrylate anhydride (MA) and RGD peptide were employed to synthesize RGD-HAMA. Subsequently, SeNPs@MM was loaded into RGD-HAMA by microfluidic device and fabricated into microspheres, namely SeNPs@MM@HMs. In vivo imaging system (IVIS) revealed prolonged intra-articular retention of SeNPs@MM@HMs. The released SeNPs@MM specifically targeted macrophages and eliminated ROS, thereby inhibiting M1 polarization. Further mechanistic investigations revealed that SeNPs@MM@HMs restrained the activation of STING/NF-κB pathway and STING/IRF-3 pathway and the expression of inflammatory factors in macrophages by stimulating Nrf2/GPX4 pathway. In addition, SeNPs@MM@HMs effectively scavenged intracellular ROS and prevented M1 polarization through regulating the Nrf2/GPX4 axis. At the chondrocyte level, conditional medium from SeNPs@MM@HMs-treated M1 macrophages suppressed oxidative stress, mitochondrial dysfunction and apoptosis of chondrocytes, while maintained ECM metabolic homeostasis. In vivo experiment results demonstrated that SeNPs@MM@HMs reduced M1 macrophage infiltration and alleviated cartilage degeneration. Collectively, this study proposed a composite microgel system that orchestrated specific targeting, ROS scavenging, macrophage repolarization, and ECM protection through spatiotemporal control of SeNPs@MM release, thus offering new therapeutic perspectives for OA management.

Note:
Funding declaration: This study was supported by grants from the Natural Science Foundation of Henan (No.232300420001, No.252300420099), Key Research Projects of Higher Education of Henan (No. 25A320022), and National Natural Science Foundation of China (No: U1304804).

Conflict of Interests: The authors declare no conflict of interest.

Ethical Approval: Animal experiments were carried out under the approval of the Ethical Committee for Animal Experiments of The First Affiliated Hospital of Zhengzhou University.

Keywords: Biomimetic nanoparticles, ROS scavenging, SeNPs, RGD peptide, Osteoarthritis