CD44-targeted hyaluronic acid nanohydrogels enhance macrophage uptake and preserve the anti-inflammatory efficacy of dexamethasone.

Abstract

The inflammatory response is among the most critical drivers of tissue damage and systemic dysfunction. Although corticosteroids (CS) can achieve symptom remission and prevent tissue damage, systemic side effects are an issue due to the lack of targeted drug delivery. To this end, we propose a new approach to delivering CS via a hyaluronic acid (HA)-cholesterol nanohydrogel (NHs). Cholesterol, responsible for the formation of NHs, facilitates interactions with CS, while HA interacts with CD44, which is overexpressed on inflammatory cells. The aforementioned NHs were shown to efficiently load dexamethasone (DEX), with 75% drug entrapment efficiency without inducing cytotoxicity in the murine macrophage RAW 264.7 cell line. The ability of DEX to reduce inflammatory cytokine levels in lipopolysaccharide-activated RAW 264.7 cells remained intact when it was loaded into NHs. The empty NHs themselves exhibited anti-inflammatory activity, likely due to the high molecular weight of the HA used in the formulation. Finally, further investigation into the role of HA in immune cell uptake revealed significantly higher internalization by activated macrophages, driven by HA-CD44 interactions, which could enable improved cellular targeting. This nanohydrogel system offers a promising, easily manufactured, and highly biocompatible solution for anti-inflammatory drug delivery.