Chemically programmed nanozyme with microenvironment remodeling for combinatorial treatment of osteoarthritis

•The prepared KGN@HMZC@HA nanozymes with high-performance SOD-like and CAT-like activity.•The on-demand release of KGN in response to the OA environment.•Chemically programmable strategy that remodels the microenvironment for managing OA.•Outstanding OA treatment efficiency and reliable biosafety. Restoring the equilibrium of joint homeostasis is crucial in treating osteoarthritis (OA). However, current strategies are primarily concentrated on individual interventions aimed at improving joint lubrication, reducing inflammation, eliminating reactive oxygen species, and stimulating cartilage differentiation, resulting in unsatisfactory therapeutic efficacy. In this work, a kind of Zn-doped hollow mesoporous CeOx (HMZC) is prepared by a facile two-step method to efficiently encapsulate the kartogenin (KGN), and then HA as a “gatekeeper” is wrapped on the surface of HMZC to generate KGN@HMZC@HA nanozymes. Since the formation of additional oxygen vacancies in the Zn-doping procedure, enabling the KGN@HMZC@HA with SOD-like and CAT-like catalytic activities. The prepared KGN@HMZC@HA can achieve the controlled KGN release in response to the specific OA environment, and chemically programmed OA microenvironment (i.e., microenvironment remodeling) by effective ROS scavenging, O2 production, macrophages transformation of M1 to M2 phenotype, and inflammation suppression. Both cellular and in vivo findings manifest the promising treatment efficiency and minimal adverse effect of the chemically programmed nanozyme for OA therapy, showing its tremendous potential as a desirable treatment option for OA.