Biomimetic micelles to accurately regulate the inflammatory microenvironment for glomerulonephritis treatment. (July 2022)

• Record Type: Journal Article
• Authors: Zhang, Huijuan; He, Qingqing; Wang, Jingjing; Wang, Yaping; Xuan, Xiangyang; Sui, Mingli; Zhang, Zhenzhong; Hou, Lin
• Is Part Of: Pharmacological research. Volume 181(2022)
• Publication Date: 2022-07
• Subjects: DXM Dexamethasone -- HA hyaluronic acid -- DMAP 4-dimethylaminopyridine -- FITC Fluorescein isothiocyanate -- MM M1 type Macrophage membrane -- NDDS Nano-drug delivery system -- CKD Chronic Kidney Diseases -- RAW264.7 Macrophages -- HBZY-1 Glomerular mesangial cell; Glomerulonephritis -- Biomimetic nanomicelles -- PH-sensitive -- Homologous targeting -- Collaborative anti-inflammatory therapy; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106263
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: 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. Graphical Abstract: ga1 Highlights: MM/HA-DXM can actively "homing" to inflammatory glomerulus. Weakly acidic microenvironment triggered dissociation of MM/HA-DXM to release DXM and HA in situ. DXM and HA can synergistically exert glomerulonephritis treatment effect via the "two-pronged" approach.