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

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.