| Rheumatoid arthritis（RA）is a common chronic autoimmune disease that can cause arthritis,progressive articular cartilage destruction and bone erosion.RA is ubiquitous all over the world.If it is not treated early,patients are easily disabled,which severely reduces their quality of life.However,the disease is still unclear,but studies have found that M1 macrophages that secrete various inflammatory cytokines play an important role in the pathogenesis of RA.By changing the microenvironment of synovial macrophages to eliminate pro-inflammatory M1 macrophages or transform them into anti-inflammatory M2 phenotypes,it is an effective method to alleviate the inflammation of RA.In our experiments,we found that polydopamine（PDA）can effectively generate oxygen（O2）and eliminate reactive oxygen species（ROS）,while the increase in O2 or decrease in ROS in the synovium of RA patients can induce the polarization of macrophages to M2 type.Methotrexate（MTX）is currently one of the most commonly used anti-rheumatic drugs in the treatment of RA.Traditional oral preparations have low bioavailability and large systemic side effects.Injection preparations are also limited due to their short intra-articular half-life and frequent injections.Its use.The pathogenesis of RA is so complicated that it is difficult to completely alleviate RA through the use of an interfering molecule.Here,we put both PDA and MTX into an injectable thermally responsive lipid gel（LG）,and then injected into the joint to form a drug reservoir PDA/MTX@LG to treat RA together.As a therapeutic agent,PDA nanoparticles can effectively generate oxygen and eliminate ROS,thereby polarizing macrophages in the RA model toward M2.As a folic acid antagonist with anti-inflammatory properties and a drug that inhibits the proliferation of blood vessels in the synovium,MTX can directly promote the death of M1macrophages,and as a traditional antirheumatic drug,it can effectively improve symptoms and delay the progression of the disease.LG thermally responsive hydrogel has unique rheological properties,which makes it exhibit superior cartilage protection and joint lubrication capabilities.In addition,the good degradability and thermal responsiveness of LG gel provide the possibility of controlling long-term drug release.Experiments have found that PDA generates mild heat under NIR radiation,which induces a reversible gel-sol phase transition of the hydrogel,thereby realizing the long-term effective release of MTX.When RA acutely attacks,the expression of matrix metalloproteinase（MMP）is up-regulated,gel degradation is accelerated,and more MTX is released from the reservoir.At the same time,the released PDA nanoparticles can also synergistically reduce the damage caused by inflammation.Conversely,when NIR irradiation is not used or inflammation is reduced,the gel reservoir will be locked and the drug release will stop.This strategy emphasizes controllable drug release and long-term anti-inflammatory and anti-rheumatic,and can achieve the desired expected dosage regimen according to the different needs of patients.Both in vivo and in vitro studies have shown that this comprehensive control strategy provides potential possibilities for on-demand administration and combined anti-inflammatory and anti-rheumatic treatments.MTX/PDA shows great therapeutic potential in the rat RA model.This research will broaden the immunotherapy strategies of RA,build an individualized drug delivery system,and provide theoretical basis and new ideas for the treatment of clinical rheumatoid arthritis. |
