CD44‐Targeted Delivery of Melittin and Celecoxib via Hyaluronic Acid‐Coated Polymersomes for Synergistic Anti‐Inflammatory Therapy

Activated macrophages are key effector cells in inflammatory diseases, but the therapeutic use of membrane-active agents such as melittin (MEL) is limited by nonspecific cytotoxicity and hemolysis. Here, we developed a hyaluronic acid (HA)-coated MEL-based polymersome (PMHA) for CD44-targeted codelivery of MEL and celecoxib (CXB). MEL was incorporated into the vesicular membrane, whereas CXB was loaded into the hydrophobic domain. PMHA showed a hydrodynamic diameter of 265.5 ± 1.6 nm, a zeta-potential of -21.14 ± 1.1 mV, a CXB encapsulation efficiency of 70.81 ± 4.18%, and a drug loading capacity of 12.87 ± 1.92%. In lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, anti-CD44 antibody blocking reduced Alexa Fluor 647-labeled PMHA uptake by approximately 37.5%, supporting HA-CD44-mediated internalization. PMHA reduced MEL-associated cytotoxicity and hemolytic activity and enabled pH-responsive CXB release. Codelivery of MEL and CXB suppressed cyclooxygenase-2 (COX-2) and tumor necrosis factor-α (TNF-α) expression, with combination index (CI) values of 0.48 and 0.67, respectively. These findings support further evaluation of PMHA as a macrophage-targeted anti-inflammatory nanoplatform.