Locally Injectable, ROS‐Scavenging, and ROS‐/pH‐Responsive Polymeric‐Micelles‐Embedded Hydrogels for Precise Minimally Invasive and Long‐Lasting Rheumatoid Therapy

Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovitis, bone‐erosion, and joint‐destruction. Here, we developed a locally injectable, ROS‐scavenging, and ROS‐/pH‐responsive drug‐delivery platform (HC@PTM) by bio‐compositing of aldolizing hyaluronic acid (HA) crosslinked with chitosan (CS), and ROS‐triggered/eliminated micelles (PTM) coupled with the drug methotrexate(MTX). The PTM efficiently eradicate excessive ROS in RA‐joints, precisely triggering drug‐release within inflamed arthritic‐sites and further confer exceptional antioxidant origins to HC@PTM. HC@PTM with outstanding shape‐adaptability and self‐repairing properties effectively conformed to irregular articular cartilage while resisting joint‐induced deformations. Further, the platform's pH‐responsive nature enables on‐demand drug‐release within acidic inflamed synovium, serving as a drug‐reservoir for precise and sustained therapeutic effects. Extensive in vitro and in vivo investigations confirm HC@PTM's ability to induce M2 macrophage polarization, downregulate inflammatory factor expression, and ameliorate the RA‐microenvironment, ultimately achieving synergistic therapeutic outcomes. This study represents significant advancements in precise and long‐term RA‐treatment through a minimally invasive approach, offering potential strategies for novel precision medicine.