A supramolecular assembly strategy for the treatment of rheumatoid arthritis with ultrasound-augmented inflammatory microenvironment reprograming.

As regulators and promotors of joint erosion, pro-inflammatory M1-like macrophages play pivotal roles in the pathogenesis of rheumatoid arthritis (RA). Here, we develop a supramolecular self-assembly (PCSN@MTX) of molybdenum (Mo) based polyoxometalate (POM), β-cyclodextrin (β-CD), and methotrexate (MTX), in which the MTX is loaded by host-guest interaction. PCSN@MTX shows inhibition of synovial M1-like macrophages polarization to alleviate RA. PCSN@MTX has demonstrated ultrasound (US) augmented catalytic behavior in consuming ROS and generating oxygen (O₂) with accelerated conversion of Mo⁵⁺ to Mo⁶⁺ in the POM. In the collagen-induced arthritis mouse model, after systemical administration, the pH-responsive PCSN@MTX shows enhanced accumulation in the acidic joints by in-situ self-assembly. The host-guest complexation between MTX and β-CD is broken via US, achieving an on-demand burst release of MTX. The released MTX and ROS-scavenging synergistically facilitate the M1-to-M2 macrophage phenotype switching, which effectively alleviates RA disease progress under US irradiation. This study provides a paradigm for RA therapy with a promising US-augmented strategy.