The co-delivery of nanoparticles encapsulating gene therapies and chemotherapeutic drugs can achieve synergistic treatment and reduce side effects in normal tissues relative to the systemic use of single drug delivery. Activated macrophages play a fundamental role in the pathogenesis of rheumatoid arthritis (RA). Hyaluronic acid (HA), a natural polysaccharide, is a specific ligand for CD44 that is overexpressed on the surface of activated macrophages. In this study, HA-coated pH-responsive nanoparticles loaded with MCL-1 small interfering RNA (siRNA) and dexamethasone (HNPs/MD) were developed for RA treatment. The HNPs/MD had a mean particle size of 117.07 ± 2.21 nm and zeta potential of 15.53 ± 1.06 mV. The release rates of both MCL-1 siRNA and dexamethasone from the HNPs/MD at pH 4.5 and 6.0 were higher than those at pH 7.4, indicating that the nanoparticles were acid-sensitive. Cytotoxicity assays showed that compared with single drug loaded nanoparticles, the HNPs/MD showed higher cytotoxicity to activated macrophages. The superior therapeutic effect of HNPs/MD was demonstrated in an adjuvant-induced arthritis rat model. These findings indicate that pH-sensitive and HA-targeting co-delivery nanoparticles provide a new direction for the therapy of RA.Copyright © 2020. Published by Elsevier B.V.