An injectable ROS-responsive hydrogel comprising chondroitin sulfate@resveratrol liposome package for osteoarthritis alleviation.

Osteoarthritis (OA) is a complex and multifactorial joint disorder. Currently, there are few therapies to slow the progression of OA. Combining symptomatic slow-acting drugs and reactive oxygen species (ROS) scavenging reagents in the inflamed joint shows a promising therapeutic approach for OA. Nonetheless, the short residence time of free drugs in the joint cavity hinders their further application. Herein, an injectable composite of hydrogel and chondroitin sulfate@resveratrol liposome package (Gel/Lip@Res + Chs) was developed to improve drug residency ability and enable the simultaneous delivery of hydrophilic Chs and hydrophobic Res in the joint cavity. This injectable hydrogel, based on phenylboronic acid modified hyaluronic acid (HAPBA) and polyvinyl alcohol (PVA), provided ROS-responsive decomposition property and sustained drug release behavior, thereby effectively scavenging ROS, promoting macrophage repolarization, and decreasing the expression of inflammatory mediators and matrix-degrading enzymes in vitro. As a proof of concept, the in vivo therapeutic efficacy of Gel/Lip@Res + Chs was further examined in both monoiodoacetic acid (MIA)-induced and surgical anterior cruciate ligament transection (ACLT)-induced OA mouse models. Benefiting from the extended residence time of loaded drugs in the joint cavity, the Gel/Lip@Res + Chs treatment could effectively suppress cartilage degeneration and increase the synthesis of the cartilage matrix, thus slowing the advancement of OA. The present study provides a reference for improving drug retention and holds great potential for treating OA-related diseases.