Acute respiratory distress syndrome (ARDS) is a severe respiratory disease that greatly threatens life and reduces the survival quality of patients [1]. The pathological mechanism of ARDS is complicated, involving a variety of inflammatory cells and mediators which can trigger inflammatory cascade reactions, destroy lung barriers, and further cause respiratory disorders. The latest guideline for the diagnosis and treatment of ARDS points out that early control of inflammation is of great significance for improving the oxygenation of patients and saving lives [2]. Dexamethasone sodium phosphate (DSP) is a commonly used glucocorticoid in clinics for inflammatory disease treatment [3]. Despite showing great potential for ARDS therapy, it has poor selectivity with many side effects at high incidence [4,5]. Glucocorticoids can cause adverse reactions in multiple organs and systems, including neutrophilia in the blood system, osteoporosis, hyperglycemia, and gastrointestinal bleeding [6]. Moreover, glucocorticoids can result in a dose-dependent increase in the risk of infection and may induce fatal infection at large doses. It is worth noting that ARDS patients are more prone to develop multiple organ dysfunction, which may amplify the side effects of drugs [7]. Therefore, exploring novel drug delivery systems to improve the targeting ability of drugs and reduce the side effects of glucocorticoids is of important clinical value and translational prospects. However, the drug delivery efficiency to the lungs is often limited, and it is difficult for a single drug to prevent the progression of the inflammatory cascade efficaciously. Thus, searching for effective drug delivery systems to achieve enhanced delivery to inflammatory lungs may provide new thoughts for ARDS medication.

Under the pathophysiological conditions of ARDS, the impaired lung air-blood barrier and the intricate inflammatory microenvironment may hinder the entry and penetration of drugs into the lesions, thereby exerting an influence on drug efficacy [8,9]. The phenomenon of increased vascular permeability and inflammatory cell uptake of nanosystems at inflamed sites was described by Wang et al. as the ELVIS effect (Extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration) [[10], [11], [12], [13]]. The loss of pulmonary endothelial/epithelial barrier integrity and excessive production of inflammatory mediators could increase pulmonary vascular/epithelial permeability, leading to the ELVIS effect in ARDS lungs [14,15]. Due to the particle size distribution in the nanoscale, nanocarriers can achieve passive targeting by taking advantage of the leaky vasculature in injured tissues [16,17]. Moreover, ARDS caused by sepsis or trauma is usually featured with severe metabolic acidosis, which can induce respiratory acidosis, release lactic acid and carbon dioxide, destroy normal cell function, and lead to lower pH in the inflammatory microenvironment compared with normal tissues [18]. It has been confirmed that the acidification of alveolar fluid is related to the progression of pulmonary inflammation. In normal conditions, the pH of the alveolar fluid is 6.9, while it can be reduced to 5.6–6.2 in ARDS patients. In addition, low pH values have been found in organelles such as endosomes, lysosomes, and Golgi apparatus, displaying different internal acidic microenvironments (pH 4.5–6.7) [19,20]. In this regard, pH-responsive nanomaterials have shown great potential in ARDS treatment [[21], [22], [23]]. In summary, the design of drug delivery systems based on the ELVIS effect at the inflammatory site, as well as the characteristics of the acidic microenvironment of ARDS may promote drug targeting and pH-responsive release, which is expected to enhance the therapeutic outcomes.

DSP can directly react with Ca2+ and form precipitates, but these precipitates are of large particle sizes with poor stability. Inspired by natural biological mineralization and based on our previous research on zinc phosphate nanoparticles [24,25], DSP and Ca2+-based mineralized nanoparticles were fabricated here to achieve stable drug encapsulation and pH-responsive drug release behavior. To further improve their biodistribution and biocompatibility [10], biomimetic modification was applied by introducing macrophage membranes [26,27]. Compared with M1 macrophages, M2 macrophages may express more protein receptors related to inhibiting inflammatory responses and exerting anti-inflammatory potencies [28,29]. Considering the essential traits of M2 macrophages in inflammation resolution, their derived membrane vesicles were selected for biomimetic modification in this design. So far, the application of M2 macrophage-derived biomimetic drug delivery systems for ARDS treatment has not been widely explored. Taking advantage of the key pathological features of increased pulmonary vascular permeability and decreased pH in pulmonary, pH-responsive hybrid mineralized vesicles (MM@LCaP) based on M2 macrophage membranes (MM) were conceived for ARDS therapy (Scheme 1). This study is established according to the critical clinical needs and dominating pathological characteristics, aiming to integrate the advantages of nanotechnology and bionics. It may contribute a new strategy to overcome the limitations of current treatments and promote clinical translation and application of nanomedicine for ARDS therapy.