Copper-based targeted nanozyme platform with sequential phototherapy-enzymatic therapy for orchestrating macrophage homeostasis in rheumatoid arthritis

Rheumatoid arthritis (RA) remains a formidable clinical challenge due to the vicious cycle of hyperactivated M1 macrophages, excessive reactive oxygen species (ROS), and sustained pro-inflammatory cytokine storm. Herein, we rationally engineered a targeted copper-based nanozyme platform (CPPF NPs) with sequential dual-wavelength phototherapy-enzymatic activities for spatiotemporally controlled macrophage homeostasis regulation in RA treatment. The CPPF NPs are fabricated via a stepwise surface engineering strategy, consisting of a copper-based nanozyme core with intrinsic superoxide dismutase (SOD)- and catalase (CAT)-like cascade activities, a polydopamine (PDA) photothermal conversion layer, a porphyrin (Por) photosensitizer, and a folic acid (FA) targeting ligand. Via FA-mediated active targeting toward M1 macrophages overexpressing folate receptors, CPPF NPs selectively accumulate in inflamed joints. Upon sequential laser irradiation, CPPF NPs first exert photodynamic therapy (PDT, 660 nm) to trigger rapid apoptosis of pro-inflammatory M1 macrophages, cutting off the source of inflammation at an early stage. Subsequently, mild photothermal therapy (PTT, 808 nm) cooperates with the inherent antioxidant nanozyme activity to scavenge residual ROS, upregulate heat shock protein 70 (HSP70) expression, and redirect residual macrophages toward the anti-inflammatory M2 phenotype. Such an “apoptosis induction–immune remodeling” sequential strategy effectively breaks the vicious cycle of oxidative stress and inflammation, thereby effectively remodeling the RA microenvironment. This work presents an integrated and biosafe nanotherapeutic strategy for precise and sequential treatment of RA, offering a promising paradigm for the intervention of other inflammation-related diseases. A functionalized copper nanozyme platform achieves spatiotemporally controlled sequential therapy: 660 nm photodynamic clearance of pro-inflammatory M1 macrophages, followed by 808 nm mild photothermal synergized with SOD/CAT cascade nanozyme activity to drive anti-inflammatory M2 polarization, effectively ameliorating rheumatoid arthritis.