Hybrid biomineralized nanovesicles to enhance inflamed lung biodistribution and reduce side effect of glucocorticoid for ARDS therapy.

Acute respiratory distress syndrome (ARDS) is a critical illness characterized by severe lung inflammation. Improving the delivery efficiency and achieving the controlled release of anti-inflammatory drugs at the lung inflammatory site are major challenges in ARDS therapy. Taking advantage of the increased pulmonary vascular permeability and a slightly acidic-inflammatory microenvironment, pH-responsive mineralized nanoparticles based on dexamethasone sodium phosphate (DSP) and Ca2+ were constructed. By further biomimetic modification with M2 macrophage membranes, hybrid mineralized nanovesicles (MM@LCaP) were designed to possess immunomodulatory ability from the membranes and preserve the pH-sensitivity from core nanoparticles for responsive drug release under acidic inflammatory conditions. Compared with healthy mice, the lung/liver accumulation of MM@LCaP in inflammatory mice was increased by around 5.5 times at 48 h after intravenous injection. MM@LCaP promoted the polarization of anti-inflammatory macrophages, calmed inflammatory cytokines, and exhibited a comprehensive therapeutic outcome. Moreover, MM@LCaP improved the safety profile of glucocorticoids. Taken together, the hybrid mineralized nanovesicles-based drug delivery strategy may offer promising ideas for enhancing the efficacy and reducing the toxicity of clinical drugs.

In situ neutrophil apoptosis and macrophage efferocytosis mediated by Glycyrrhiza protein nanoparticles for acute inflammation therapy.

In the progression of acute inflammation, the activation and recruitment of macrophages and neutrophils are mutually reinforcing, leading to amplified inflammatory response and severe tissue damage. Therefore, to regulate the axis of neutrophils and macrophages is essential to avoid tissue damage induced from acute inflammatory. Apoptotic neutrophils can regulate the anti-inflammatory activity of macrophages through the efferocytosis. The strategy of in situ targeting and inducing neutrophil apoptosis has the potential to modulate macrophage activity and transfer anti-inflammatory drugs. Herein, a natural glycyrrhiza protein nanoparticle loaded with dexamethasone (Dex@GNPs) was constructed, which could simultaneously regulate neutrophil and macrophage function during acute inflammation treatment by combining in situ neutrophil apoptosis and macrophage efferocytosis. Dex@GNPs can be rapidly and selectively internalized by neutrophils and subsequently induce neutrophils apoptosis through a ROS-dependent mechanism. The efferocytosis of apoptotic neutrophils not only promoted the polarization of macrophages into anti-inflammatory state, but also facilitated the transfer of Dex@GNPs to macrophages. This enabled dexamethasone to further modulate macrophage function. In mouse models of acute respiratory distress syndrome and sepsis, Dex@GNPs significantly ameliorated the disordered immune microenvironment and alleviated tissue injury. This study presents a novel strategy for drug delivery and inflammation regulation to effectively treat acute inflammatory diseases.

Engineered Biomimetic Nanovesicles Based on Neutrophils for Hierarchical Targeting Therapy of Acute Respiratory Distress Syndrome.

Acute Respiratory Distress Syndrome (ARDS) is a clinically severe respiratory disease that causes severe medical and economic burden. To improve therapeutic efficacy, effectively targeting delivery to the inflamed lungs and inflamed cells remains an ongoing challenge. Herein, we designed engineered biomimetic nanovesicles (DHA@ANeu-DDAB) by fusion of lung-targeting functional lipid, neutrophil membrane containing activated ß2 integrins, and the therapeutic lipid, docosahexaenoic acid (DHA). By the advantage of lung targeting lipid and ß2 integrin targeting adhesion, DHA@ANeu-DDAB can first target lung tissue and further target inflammatory vascular endothelial cells, to achieve "tissue first, cell second" hierarchical delivery. In addition, the ß2 integrins in DHA@ANeu-DDAB could bind to the intercellular cell adhesion molecule-1/2 (ICAM-1/2) ligand on the endothelium in the inflamed blood vessels, thus inhibiting neutrophils' infiltration in the blood circulation. DHA administration to inflamed lungs could effectively regulate macrophage phenotype and promote its anti-inflammatory activity via enhanced biosynthesis of specialized pro-resolving mediators. In the lipopolysaccharide-induced ARDS mouse model, DHA@ANeu-DDAB afforded a comprehensive and efficient inhibition of lung inflammation and promoted acute lung damage repair. Through mimicking physiological processes, these engineered biomimetic vesicles as a delivery system possess good potential in targeting therapy for ARDS.

Spatial characteristics and coupling coordination between carbon emission efficiency and industrial structure in three metropolitan areas of Jiangsu Province, China.

It is of great practical significance to study the spatial characteristics of carbon emission efficiency, industrial structure, their coupling and coordination relationship for China's green development and industrial structure transformation in the new era. From the perspective of coupling, coordination and space, this paper analyzes and summarizes the spatial characteristics of carbon emission efficiency and industrial structure of 19 cities in three metropolitan areas of Jiangsu Province during 2009-2019 and their coupling and coordination relationship. The carbon emission efficiency in this study is represented by the carbon emission economic efficiency index and carbon emission social efficiency index. The results show that (a) the high-emission centers in the three metropolitan areas developed from "three centers" in 2009 to "five centers" in 2019. The continuous high-energy consumption of the secondary industry and the growth of the economic aggregate of the third industry kept the regional high carbon dioxide emissions. (b) The average value of carbon emission economic efficiency in 19 cities continued to increase, indicating that the contribution rate of the same amount of carbon emissions to economic income gradually increased; the growth range of carbon emission economic efficiency index is greater than that of carbon emission social efficiency index, indicating that carbon emission has a more significant effect on the improvement of regional economic development than on the improvement of public service level and residents' living quality. (d) The solidification degree of carbon emission efficiency is greater than that of the industrial structure (solidification degree carbon emission social efficiency > carbon emission economic efficiency > industrial structure). The high-grade industrial structure in Xuzhou metropolitan area is closely related to the improvement of carbon emission economic efficiency and carbon emission social efficiency, and both are in moderate antagonism. The rationalizing industrial structure in Nanjing metropolitan area is closely related to the improvement of carbon emission economic efficiency, which is in high coordination run-in. The concentration degree of industrial structure in Suzhou-Wuxi-Changzhou metropolitan area is closely related to the improvement of carbon emission economic efficiency and carbon emission social efficiency, which are in polar coordination coupling and high coordination run-in, respectively. The proposed coupling path of carbon emission efficiency-industrial structure can not only alleviate the dynamic disharmony in different cities but also effectively improve the coupling degree in cities.