A Mg-Al layered double hydroxide-based nanocomposite functionalized with PTHrP-2 and loaded with polyoxometalates for osteoarthritis therapy.

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degeneration, inflammation, and oxidative stress. Existing monotherapies exhibit limited efficacy as they fail to comprehensively address the disease's complex pathological features. This study developed a multifunctional nanocomposite (LDH-P@P2) based on magnesium-aluminum layered double hydroxide (LDH) loaded with a molybdenum-based polyoxometalate (POM) and the parathyroid hormone-related peptide-2 (PTHrP-2) for OA treatment. The nanocomposite functions as a pH-responsive carrier that degrades within the acidic microenvironment of OA lesions, enabling the controlled release of magnesium ions (Mg2+), POM, and PTHrP-2. This system delivers multi-pathway synergistic therapeutic effects including reactive oxygen species (ROS) scavenging, promotion of chondrocyte proliferation, inhibition of apoptosis, immunomodulation via macrophage polarization, regulation of osteogenic differentiation, and amelioration of the acidic microenvironment. Transcriptome sequencing revealed that the therapeutic mechanism primarily involves activation of the PI3K/Akt pathway and inhibition of the MAPK pathway. In vivo experiments confirmed that intra-articular injection of LDH-P@P2 significantly alleviated OA progression in an anterior cruciate ligament transection (ACLT) rat model, reducing joint effusion and osteophyte formation while promoting cartilage matrix synthesis, improving subchondral bone structure, and demonstrating good biocompatibility. This work proposes a novel therapeutic strategy for OA that integrates multi-pathway synergy with pH-responsive targeting.