Spatiotemporally Precise Rheumatoid Arthritis Therapy via a Triple‐Locked Cascaded Nanoplatform With Dual‐Channel Self‐Reporting

ABSTRACT

Achieving precise spatiotemporal control over combination therapies in rheumatoid arthritis (RA) remains heavily compromised by conventional nanoplatforms, which typically suffer from premature off‐target leakage, coupled drug release, and inadequate in vivo tracking capabilities. Herein, a programmable orthogonally branched triple‐locked nanotheranostic platform (MB@YW NPs) is engineered to seamlessly synchronize spatial localization, chemically orthogonal multidrug liberation, and real‐time multichannel self‐reporting. The system comprises a pH‐responsive polymeric matrix co‐encapsulating a HOCl‐activatable methotrexate prodrug (MB‐MTX) and an ONOO ⁻ /light‐responsive sulfasalazine prodrug (YW‐SSZ). Precluding systemic leakage, synovial acidity dictates initial spatial targeting by triggering tissue‐specific disassembly and subsequent macrophage internalization. Subsequently, non‐interfering pathophysiological triggers exclusively liberate distinct therapeutics through independent pathways: intracellular HOCl purely unlocks methotrexate with concomitant near‐infrared “turn‐on” fluorescence, whereas an isolated ONOO ⁻ /light sequence locally activates sulfasalazine accompanied by a blue “on‐to‐off” readout. This lack of cross‐talk successfully discriminates multiplexed activation states. In vivo, this triple‐locked platform efficiently alleviates oxidative stress and remodels the inflammatory microenvironment, leading to markedly suppressed joint destruction in collagen‐induced arthritis models. Furthermore, transcriptomic analysis reveals these synergistic macroscopic benefits are driven by targeted modulation of the cAMP/NF‐κB signaling axis. Collectively, this work establishes a transformative and generalizable framework for independently coordinated, next‐generation precision multi‐prodrug nanomedicine.