A multifunctional nanoaggregate‐based system for detection of rheumatoid arthritis via Optoacoustic/NIR‐II fluorescent imaging and therapy via inhibiting JAK‐STAT/NF‐κB/NLRP3 pathways

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 H 2 O 2 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.