Abstract

Rheumatoid arthritis (RA) treatment is severely hindered by the systemic toxicity and limited joint accumulation of conventional therapeutics. To overcome these critical clinical challenges, we engineered a biomimetic dual-targeted nanoplatform (MTX@HSA@M@HA NPs) to precisely deliver methotrexate (MTX) to inflamed synovia. The rationally designed system encapsulates MTX within human serum albumin (HSA) nanoparticles, which are subsequently cloaked in red blood cell membranes (RBCMs) for robust immune evasion and prolonged systemic circulation. To achieve active targeting, the nanoparticle surface was functionalized with hyaluronic acid (HA) to selectively bind CD44 receptors, which are heavily overexpressed on RA-driving macrophages and fibroblast-like synoviocytes (FLSs). In vitro evaluations demonstrated significantly enhanced cellular internalization by activating RAW264.7 macrophages and FLS, resulting in the potent suppression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) with minimal baseline cytotoxicity. Furthermore, comprehensive in vivo studies using a collagen-induced arthritis (CIA) murine model confirmed that MTX@HSA@M@HA NPs significantly ameliorated joint inflammation, attenuated paw swelling, and rapidly improved functional outcomes compared to free MTX. By synergizing RBCM camouflage with HA-directed active targeting, this nanoplatform maximizes localized therapeutic efficacy while minimizing systemic toxicity, thereby presenting a highly promising and translatable strategy for targeted RA treatment.

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