NIR‐Triggered Hydrogen‐Thermotherapy Regulates Inflammatory Circuits Between Macrophages and Synovial Fibroblasts in Rheumatoid Arthritis

ABSTRACT The pathogenesis of rheumatoid arthritis (RA) involves complex immune and inflammatory processes, among which the self‐amplifying inflammatory feedback loop between macrophages and fibroblast‐like synoviocytes (FLS) within the rheumatoid arthritis microenvironment (RAM) is a key factor driving disease progression, fundamentally linked to immune system hyperactivation. Addressing this pathological mechanism, we present a hydrogen‐photothermal combinatorial therapy approach through a near‐infrared (NIR)‐activated nanocomposite platform engineered for concurrent hydrogen evolution and photothermal conversion. The nanocomposite platform comprises a UIO‐66‐NH 2 metal–organic framework (MOF) matrix strategically integrated with upconversion nanoparticles (UCNPs) and molybdenum disulfide (MoS 2 ) nanosheets (UCNP@MOF/MoS 2 ), creating an optimized NIR‐responsive system. Under NIR irradiation, UCNPs convert photons to UV/visible light, activating both MOF for photocatalytic hydrogen production and MoS 2 for photothermal effects. The released hydrogen scavenges ROS, reduces oxidative stress, and polarizes pro‐inflammatory M1 macrophages toward anti‐inflammatory M2 phenotypes. Concurrently, the combined therapy suppresses immune hyperactivation and inflammatory cell infiltration. This dual approach disrupts the M1 macrophage‐FLS inflammatory feedback loop in the RA microenvironment. In RA rat models, the treatment reduced joint swelling, synovial hyperplasia, and cartilage damage while restoring microenvironmental balance. These results demonstrate the therapeutic potential of hydrogen‐photothermal combinatorial therapy for RA.