The ROS‐responsive Scavenger with Intrinsic Antioxidant Capability and Enhanced Immunomodulatory Effects for Cartilage Protection and Osteoarthritis Remission

Oxidative stress has close relationship with the progression of osteoarthritis and thus is an important therapeutic target. The use of antioxidants alone has common disadvantages such as low bioavailabil-ity, poor stability, and rapid joint clearance or toxicity at high concentrations. To achieve both reactive oxygen species (ROS) responsive scavenging ability and drug targeted delivery ability, a novel polymer (PEG-PTK-PEG) was synthesized through a simple and direct reaction between polythioketal (PTK) and m-PEG-acrylate. In addition to excellent mechanical properties and high drug loading capacity, the degra-dation products of PEG-PTK-PEG responding to the ROS accumulating microenvironment also have excel-lent biocompatibility and extremely low toxicity. Further, the PEG-PTK-PEG nanoparticles (NPs) loaded with astaxanthin (ASTA), which is an antioxidant with high biological safety, could effectively reduce ROS expression and release ASTA slowly and accurately in the area of high ROS expression as a result of the polymer degradation. In the OA model, the PEG-PTK-PEG@ASTA could effectively inhibit the expression of ROS, thereby downregulating the MAPK signaling pathway and inducing the conversion of macrophages from the M1 phenotype to the M2 phenotype. The synergistic effect of PEG-PTK-PEG's ROS-responsive drug delivery ability and ROS scavenging ability significantly promoted the therapeutic effect of OA, pro-viding a new and effective strategy for the clinical treatment of OA. (c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )