Rod-Shaped Nanotherapeutics Alleviate Rheumatoid Arthritis by Precisely Disrupting Platelet-Mediated Pathological Crosstalk via a Morphology-Dependent Manner.

Abstract

During flares of rheumatoid arthritis (RA), activated platelets (PLTs) amplify inflammatory cascades and drive disease progression by extensively engaging in pro-inflammatory crosstalk with inflammatory cells. Precisely disrupting PLT-mediated pathological cellular crosstalk has emerged as promising therapeutics. Existing PLT-targeting strategies primarily rely on the ligand-mediated recognition, overlooking the hemodynamic behavior of circulating PLTs. Under blood flow, PLTs preferentially roll along vascular walls, while conventional nanocarriers tend to flow along the central axis. This inherent spatial separation limits their targeting efficiency. The optimization of nanoparticle geometry provides a potential solution by enabling precise control over their flow trajectories in circulation. Herein, the study designs fucoidan-functionalized nanoplatforms with different morphologies and comparatively explores their targeting efficiency and regulatory activity in PLTs. In a microfluidic flow model, rod-shaped nanoparticles exhibit markedly enhanced co-localization with endothelial-adherent PLTs. Moreover, these rod-shaped nanoparticles inhibit focal adhesion kinase (FAK) and PI3K/AKT signaling in a morphology-dependent manner, thereby effectively disrupting their pathological cellular crosstalk. In arthritic rats, intravenously administered resveratrol-loaded nanorod (PNR@Res) efficiently binds circulating PLTs and accumulates in inflamed joints, ultimately effectively alleviating RA symptoms. The findings offer insight into how nanoparticle geometry governs cell interactions with circulating PLTs and influences PLT pathological behaviors through a morphology-dependent mechanism in inflammatory diseases.