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Abstract Rheumatoid arthritis (RA) is a debilitating autoimmune disease that causes chronic pain and serious complications, presenting a significant challenge to treat. Promising approaches for treating RA involve signaling pathways modulation and targeted therapy. To this end, a multifunctional nanosystem, TPC‐U@HAT, has been designed for RA therapy, featuring multitargeting, dual‐stimuli response, and on‐demand drug release capabilities. TPC‐U@HAT is composed of a probe/prodrug TPC, a JAK1 kinase inhibitor upadacitinib, and the drug carrier HAT. TPC is composed of an aggregation‐induced emission (AIE)‐active NIR‐II chromophore TPY and an NF‐κB/NLRP3 inhibitor caffeic acid phenethyl ester (CAPE), connected via boronic ester bond which serves as the reactive‐oxygen‐species‐responsive linker. The carrier, HAT, is created by grafting bone‐targeting alendronate and hydrophobic tocopheryl succinate onto hyaluronic acid chains, which can encapsulate TPC and upadacitinib to form TPC‐U@HAT. Upon intravenous injection into mice, TPC‐U@HAT accumulates at inflamed lesions of RA through both active and passive targeting, and the overexpressed hyaluronidase and H2O2 therein cleave the hyaluronic acid polymer chains and boronate bonds, respectively. This generates an AIE‐active chromophore for detection and therapeutic evaluation of RA via both optoacoustic imaging and NIR‐II fluorescent imaging and concomitantly releases CAPE and upadacitinib to exert efficacious therapy by inhibiting NF‐κB/NLRP3 and JAK‐STAT pathways.

The development of stimuli-responsive polymeric micelles for targeted drug delivery has attracted much research interest in improving therapeutic outcomes. This study designs copolymers responsive to ultraviolet (UV) light and glutathione (GSH). A disulfide linkage is positioned between a hydrophilic poly(ethylene glycol) monomethyl ether (mPEG) and a hydrophobic o-nitrobenzyl methacrylate (ONBMA) to yield amphiphilic copolymers termed mPEG-SS-pONBMA. Three copolymers with different ONBMA lengths are synthesized and formulated into micelles. An increase in particle size and a decrease in critical micelle concentration go together with increasing ONBMA lengths. The ONB cleavage from mPEG-SS-pONBMA-formed micelles results in the transformation of hydrophobic cores into hydrophilic ones, accelerating drug release from the micelles. Obvious changes in morphology and molecular weight of micelles upon combinational treatments account for the dual-stimuli responsive property. Enhancement of a cell-killing effect is clearly observed in doxorubicin (DOX)-loaded micelles containing disulfide bonds compared with those containing dicarbon bonds upon UV light irradiation. Collectedly, the dual-stimuli-responsive mPEG-SS-pONBMA micelle is a better drug delivery carrier than the single-stimuli-responsive mPEG-CC-pONBMA micelle. After HT1080 cells were treated with the DOX-loaded micelles, the high expression levels of RIP-1 and MLKL indicate that the mechanism involved in cell death is mainly via the DOX-induced necroptosis pathway.