Bioactive phosphorus dendrimers deliver protein/drug to tackle osteoarthritis via cooperative macrophage reprogramming.

Reprogramming imbalanced synovial macrophages and shaping an immune microenvironment conducive to bone and cartilage growth is crucial for efficient tackling of osteoarthritis (OA). Herein, we present a co-delivery nanosystem based on generation 2 (G2) hydroxyl-terminated bioactive phosphorus dendrimers (G2-OH₂₄) that were loaded with both catalase (CAT) and quercetin (Que). The created G2-OH₂₄/CAT@Que complexes exhibit a uniformly distributed spherical morphology with a size of 138.8 nm, possess robust stability, and induce macrophage reprogramming toward anti-inflammatory M2 phenotype polarization and antioxidation through cooperative CAT-catalyzed oxygen generation, Que-mediated mitochondrial homeostasis restoration, and inherent immunomodulatory activity of dendrimer. Such macrophage reprogramming leads to chondrocyte apoptosis inhibition and osteogenic differentiation of bone mesenchymal stem cells. Administration of G2-OH₂₄/CAT@Que to an OA mouse model results in attenuation of pathological features such as cartilage degeneration, bone erosion, and synovitis through oxidative stress alleviation and inflammatory factor downregulation in inflamed joints. Excitingly, the G2-OH₂₄/CAT@Que also polarized macrophages in adherent effusion monocytes (AEMs) extracted from joint cavity effusions of OA patients to M2 phenotype and downregulated reactive oxygen species levels in AEMs. This study suggests a promising nanomedicine formulation of phosphorus dendrimer-based co-delivery system to effectively tackle OA through the benefits of full-active ingredients of dendrimer, drug, and protein.