Metal-Phenolic Nanocatalysts Block Transient Receptor Potential Vanilloid 1 and Regulate Bone Homeostasis for Arthritic Analgesia and Therapeutics.

Inflammatory arthritis is a chronic immune disorder characterized by synovial inflammation, pain, and progressive joint destruction, yet most current therapies focus on the regulation of a single pathological process or symptom. In the present work, we report the establishment of self-assembled strontium-caffeic acid nanoparticles (CA-Sr NPs) through metal-polyphenol coordination, which function as an integrated neuro-immune-bone modulator for inflammatory arthritis therapy. By coupling redox catalysis with TRPV1-associated Ca2+ antagonism and Sr2+-enabled osteoregulation, CA-Sr NPs exhibit combined effects of sustained reactive oxygen species scavenging and enhanced regulation of the Ca2+-permeable TRPV1 channel on macrophages and dorsal root ganglion (DRG) neurons, thus repolarizing macrophages from M1 to M2 phenotype and suppressing the pathological Ca2+ influx and neuronal hyperexcitability, respectively. Meanwhile, CA-Sr NPs promote osteoblast activity while inhibiting osteoclast differentiation. In the Complete Freund's Adjuvant-induced murine arthritis model, CA-Sr NPs markedly alleviated multiple inflammatory arthritis symptoms, including joint swelling, pain, and bone erosion. Collectively, this study highlights highly promising therapeutic potentials of CA-Sr NPs for inflammatory arthritis management and broadens the scope of metal-phenolic nanocatalysts toward treating neuro-immune-bone disorders.