Research On Cell Engineering Biomimetic Nano-gelatin Carrier In The Treatment Of Osteoarthritis

Osteoarthritis(OA)is chronic and low-grade inflammation that exists selfperpetuating cycle of local tissue damage,inflammation,and repair.M2 macrophages present an anti-inflammatory function and promote cartilage repair.However,it is a significant challenge to regulate the helpful secretion of M2 macrophages on demand toward disease-modifying osteoarthritis therapeutics.Here,artificial M2 macrophage(AM2M)with yolk-shell structure was proposed and fabricated to enhance the therapeutic efficacy of M2 macrophages in the treatment of OA.AM2 M was composed of macrophage membrane as “shell” and inflammation-responsive nanogel as “yolk”.The nanogel was prepared via physical interaction of gelatin and chondroitin sulfate(ChS)through ionic bond and hydrogen bond,achieving burst release to down-regulate inflammation during acute flares and sustainable release to repair cartilage during low inflammatory activity.Furthermore,AM2 M exhibited the targeting and long-term residence in the inflamed area and blocked the activation of macrophages by ChS.Therefore,our finding provided a new insight that artificial M2 macrophages are expected to break a vicious and self-perpetuating cycle of OA.Next,our research explored the regulatory effect of biomimetic nanoparticles on the adjustment of the M2/M1 ratio,and we found that only M1 phenotype macrophages can undergo membrane fusion with biomimetic nanoparticles.Therefore,our research hopes to specifically engineer M1 phenotype macrophages through membrane fusion between biomimetic nanoparticles and M1 phenotype.Biomimetic nanoparticles promote the transformation of M1 to M2 by IL-4.The folic acid targeting peptides of biomimetic nanoparticles is fused into the phospholipid bilayer of M1 macrophages through membrane fusion,so that the transformed M2 macrophages can produce extracellular vesicles with M1 targeting and carry excess IL-4.Further transform other M1 to M2,the macrophages in the osteoarthritis site can maintain a high M2/M1 ratio for a long time,and then achieve the effect of anti-inflammatory and cartilage repair.