ROS-responsive liposomes as an inhaled drug delivery nanoplatform for idiopathic pulmonary fibrosis treatment via Nrf2 signaling

Abstract

Background Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease with pathophysiological characteristics of transforming growth factor-β (TGF-β), and reactive oxygen species (ROS)-induced excessive fibroblast-to-myofibroblast transition and extracellular matrix deposition. Macrophages are closely involved in the development of fibrosis. Nuclear factor erythroid 2 related factor 2 (Nrf2) is a key molecule regulating ROS and TGF-β expression. Therefore, Nrf2 signaling modulation might be a promising therapy for fibrosis. The inhalation-based drug delivery can reduce systemic side effects and improve therapeutic effects, and is currently receiving increasing attention, but direct inhaled drugs are easily cleared and difficult to exert their efficacy. Therefore, we aimed to design a ROS-responsive liposome for the Nrf2 agonist dimethyl fumarate (DMF) delivery in the fibrotic lung. Moreover, we explored its therapeutic effect on pulmonary fibrosis and macrophage activation. Results We synthesized DMF-loaded ROS-responsive DSPE-TK-PEG@DMF liposomes (DTP@DMF NPs). DTP@DMF NPs had suitable size and negative zeta potential and excellent capability to rapidly release DMF in a high-ROS environment. We found that macrophage accumulation and polarization were closely related to fibrosis development, while DTP@DMF NPs could attenuate macrophage activity and fibrosis in mice. RAW264.7 and NIH-3T3 cells coculture revealed that DTP@DMF NPs could promote Nrf2 and downstream heme oxygenase-1 (HO-1) expression and suppress TGF-β and ROS production in macrophages, thereby reducing fibroblast-to-myofibroblast transition and collagen production by NIH-3T3 cells. In vivo experiments confirmed the above findings. Compared with direct DMF instillation, DTP@DMF NPs treatment presented enhanced antifibrotic effect. DTP@DMF NPs also had a prolonged residence time in the lung as well as excellent biocompatibility. Conclusions DTP@DMF NPs can reduce macrophage-mediated fibroblast-to-myofibroblast transition and extracellular matrix deposition to attenuate lung fibrosis by upregulating Nrf2 signaling. This ROS-responsive liposome is clinically promising as an ideal delivery system for inhaled drug delivery. Graphical Abstract

Arthritic Microenvironment Actuated Nanomotors for Active Rheumatoid Arthritis Therapy

“…The hypoxic microenvironment in RA joints normally induces HIF‐1 α expression, which is also reported to affect the balance of macrophage subtypes. [ 7b ] To verify the hypoxia‐attenuating ability of MnO 2 ‐motors, HIF‐1 α expression levels were then evaluated by immunofluorescence staining. After pretreatment with MnO 2 NPs, MSN@Ce, MnO 2 + Ce, and MnO 2 ‐motors, LPS‐activated RAW264.7 cells were incubated under a hypoxic chamber for 8 h. According to Figure 4d , hypoxia and LPS induced HIF‐1 α expression in RAW264.7 cells successfully, which was attenuated by the treatment with MnO 2 NPs, MSN@Ce, MnO 2 + Ce, and MnO 2 ‐motors.…”

“…[ 5 , 6 ] Meanwhile, the existing reactive oxygen species (ROS) are also closely related to the inflammation progress in arthritis, showing strong M1 activation performance through specific M1 signaling pathway (NF‐kB). [ 7 ] Therefore, to develop a new strategy for HIF‐1 α inhibition and ROS scavenging to block M1 phenotypic polarization is of great significance for RA therapy.…”

The Role of Nrf2 in Pulmonary Fibrosis: Molecular Mechanisms and Treatment Approaches

“…In addition, dimethyl fumarate 22 which has been approved for the first-line treatment of relapsing-remitting multiple sclerosis [ 175 ]; dihydroartemisinin which is traditionally used to treat malaria [ 100 ]; chloroquine 23 which has been used for malaria treatment [ 176 ]; and proton pump inhibitors such as esomeprazole 24 [ 156 ] have all been shown to inhibit the progression of PF by Nrf2 signaling. Thus, there is great potential for translating these drugs rapidly into clinical practice for treatment of PF.…”

“…Recent evidence suggests that the application of nanotechnology is expected to solve these problems. Liu et al designed a dimethyl fumarate-loaded ROS responsive liposome as an inhaled drug which presented enhanced antifibrotic effect, compared with direct dimethyl fumarate instillation [ 175 ]. This ROS-responsoftenive liposome is clinically promising as an ideal delivery system for inhaled drug delivery.…”

An ischemia-homing bioengineered nano-scavenger for specifically alleviating multiple pathogeneses in ischemic stroke

“…), and hydroxyl radical (•OH), which is another well-known crucial pathological cause of ischemic stroke [30][31][32][33]. The upregulated ROS can not only directly induce mitochondrial damage and neuron apoptosis but also serve as important signaling regulators to stimulate the activation of resident microglia and infiltrated peripheral leukocytes via the nuclear factor-κB (NF-κB) signaling pathway, thus ultimately aggravating the inflammation [20,[34][35][36][37][38][39]. Furthermore, excessive ferrous ions (Fe 2+ ) in microglia cells caused by hemolysis could continuously catalyze intracellular H 2 O 2 into •OH and •O 2 − via Fenton reactions, which is also responsible for lasting neurological impairment and ischemic injury [40].…”