Acid-responsive nanoparticles with microneedles for anti‑inflammatory sonodynamic therapy of gouty arthritis

The pathological microenvironment of acute gouty arthritis (AGA) features local tissue acidification and the release of a storm of pro-inflammatory cytokines. To address this dual challenge, we engineered an acid-responsive curcumin-loaded nanoparticles microneedle system (Cur-PNPs@MN) that delivers curcumin with pH-triggered release and anti-inflammatory activity. This integrated platform combines a hyaluronic acid (HA)-based dissolving microneedle for localized transdermal delivery of acid-degradable PCADK (poly (cyclohexane-1,4-diyl acetone dimethylene ketal)) curcumin nanoparticles (Cur-PNPs), which are designed for pH-triggered curcumin release at the pathological site. Together, they deliver curcumin, a dual-function agent acting both as an anti-inflammatory compound and a nanoenhanced sonosensitizer. In vitro, the system exhibited acid-responsive drug release and also promoted macrophage uptake, achieving significant curcumin accumulation within 1 hour and saturation by 4 hours. Moreover, it could generate potent ultrasound-induced reactive oxygen species (ROS). The ROS generation capability of Cur-PNPs was 1.47-fold higher than that of Cur‑aggregates, resulting in anapoptosis rate of 29.9% in M1 macrophages. In vivo, the chemo-sonodynamic therapy (Cur-PNPs@MN+Ultrasound (US)) in a rat AGA model significantly alleviated joint swelling and inflammatory infiltration, while drastically suppressing pro-inflammatory cytokines, with IL-1β decreasing from 170.3 to 67.3 pg/mL, TNF-α from 20.8 to 5.9 pg/mL, and IL-6 from 140.9 to 48.2 pg/mL, and achieved therapeutic efficacy comparable to conventional drugs. This work demonstrates a synergistic chemo‑sonodynamic strategy by coupling pH-triggered curcumin release with ultrasound-enhanced ROS generation. This acid-responsive therapeutic strategy enhances anti-inflammatory efficacy and reduction of M1-associated inflammatory responses, offering an effective approach for AGA therapy.