Biomimetic micelles to accurately regulate the inflammatory microenvironment for glomerulonephritis treatment

Glomerulonephritis is a key factor in leading to end-stage renal disease. Mesangial cell proliferation and macrophage infiltration are two prominent features linked in a vicious circle mechanism for glomerulonephritis progression. Herein, a novel biomimetic pH-sensitive nanomicelle (MM/HA-DXM) was constructed to synergize hyaluronic acid (HA)-activated macrophage phenotypic remodeling and dexamethasone (DXM)-mediated mesangial cell killing for precise treatment of glomerulonephritis. Owing to the camouflaged coating with endogenous macrophage membrane (MM), MM/HA-DXM could escape from RES phagocytosis and then be recruited to inflammatory glomerulus by active homing effect. Afterwards, HA-DXM nanomicelles ruptured in response to the weakly acidic glomerulonephritis microenvironment, to locally release HA and DXM . On the one hand, DXM can inhibit the abnormal proliferation of mesangial cells. On the other hand, HA transformed pro-inflammatory M1 macrophages into anti-inflammatory M2 phenotype to improve the glomerular inflammatory microenvironment. In doxorubicin-induced glomerulonephritis models, results revealed that MM/HA-DXM could specifically “homing” to inflammatory renal tissue with 4.33-fold improvement in targeting performance. In addition, in vivo pharmacodynamic results proved that after treatment with MM/HA-DXM, the proteinuria level decreased to 2.33 times, as compared with that of control group, demonstrating a superior therapeutic effect on glomerulonephritis via this collaborative two-pronged anti-inflammatory therapy strategy.