The cellular inflammatory storm is one of the main causes of severe inflammation in ALI and leads to the release of various inflammatory factors such as TNF-α, IL-6, and IL-1β (Figure 4). A promising approach is to exert anti-inflammatory effects by inhibiting the secretion of pro-inflammatory cytokines. For example, ROS-responsive polythione nanoparticles (NPs) loaded with dexamethasone (DEX) have been shown to significantly reduce the levels of the pro-inflammatory factors IL-6, TNF-α, and IL-1β. This reduction exerts an inhibitory effect on inflammation and helps alleviate acute lung injury (Zhai et al., 2022). Nanomaterials can exert anti-inflammatory effects by modulating macrophage polarization (Figure 4). One research team constructed novel NPs comprising self-assembling peptides for rapid anti-inflammatory programming (SPRAY), which self-assemble to form NPs, by screening to identify the best SPRAY candidate, namely, the peptide BLKR (Chen D. et al., 2024). These NPs were experimentally found to specifically target alveolar macrophages to promote M2 polarization and inhibit M1-related signaling. Inhibition of signaling pathways is also one of the ways in which nanomaterials exert anti-inflammatory effects, with the NF-κB signaling pathway being a central regulator of the inflammatory response (Figure 4) (Jing et al., 2015). NF-κB is the main regulatory pathway of the inflammatory response. The expression of proinflammatory cytokines and chemokines depends on NF-κB, and the expression of these factors activates neutrophils, leading to increased alveolar capillary permeability, manifested as pulmonary edema and oxygenation disorders. When ALI occurs, NF-κB can be activated by multiple factors, and its sustained activation can lead to an inflammatory storm, thereby exacerbating ALI (Zhou et al., 2023). It has been found that iron-capsaicin nanozymes are able to alleviate sepsis-induced ALI via the NF-κB signaling pathway (Wang R. et al., 2024).

Oxidative stress plays an important role in the development of ALI due to endothelial damage and capillary leakage. Nanomaterials can mitigate lung damage resulting from excessive oxidative stress by increasing antioxidant capacity and reducing the production of oxygen-containing free radicals (Laforge et al., 2020). Strategies have been developed to modulate the oxidative microenvironment in ALI using ROS-responsive nanoparticles (NPs). For instance, Muhammad et al. prepared DEX-loaded polyurethane (PFTU@DEX) NPs by a modified emulsification method and investigated their effects by using an ROS-specific bioluminescent probe (L012) to assess ROS levels in different groups in a mouse model. They concluded that the PFTU@DEX NPs significantly reduced the local expression of ROS and thus alleviated ALI (Muhammad et al., 2022). In addition, some nanomaterials possess endogenous antioxidant mechanisms. The Nrf2/antioxidant response element (ARE) signaling pathway plays an important role in the activity of endogenous antioxidants, as Nrf2 induces the action of ARE genes to prevent the production of excessive ROS (Figure 4). Recent studies have shown that various metal-based NPs (e.g., Au, TiO₂, and Ag NPs) can stimulate the Nrf2/ARE signaling pathway to achieve an antioxidant effect by increasing the levels of ROS and malondialdehyde (Xiong et al., 2022).

Gene therapy is a new type of treatment that replaces abnormal genes with normal genes, introduces new genes, or edits existing genes to combat specific diseases (Verma and Somia, 1997). Nanomaterials can be used as carriers for targeted delivery of gene drugs, retarding their degradation, extending their half-life, and improving the efficiency of their action (Salameh et al., 2020; Xin et al., 2017; Miyazawa et al., 2017; Alex et al., 2013). The delivery of specific siRNAs is a new strategy with potential for the treatment of ALI in clinical practice. Nanomaterials can deliver specific siRNAs to inhibit the expression of inflammatory genes (Figure 4). Chen et al. constructed a selenium nanozyme therapeutic system (cationic water-soluble pillar arene [CWP]-Se@mannose [Man]) loaded with C-C chemokine receptor 2 (CCR2)-siRNA. This system exhibited electroneutrality and targeting properties for lung macrophages. It was observed that the mucus permeability of CWP-Se@Man was increased by a factor of about 15. CWP-Se@Man was able to effectively penetrate the mucus layer of the lungs to deliver CCR2-siRNA into macrophages. Moreover, in an inflammatory situation, the CWP-Se@Man nanotherapeutic system loaded with CCR2-siRNA could exert an inhibitory effect on chemotaxis and was able to scavenge ROS, which could alleviate ALI (Chen X. et al., 2024). LNPs have great potential for the delivery of mRNA, and studies of LNP-mRNA complexes for the treatment of ALI are becoming increasingly widespread. Research on the inhalation delivery of mRNA also shows great potential (Jiang et al., 2024). However, LNP-mRNA complexes have the disadvantage of a low in vivo degradation rate, which limits their applicability in ALI. Another research team used the azide-acetal linkage as a platform for generating rapidly hydrolyzed (RD)-LNPs to overcome this shortcoming. It was experimentally demonstrated that RD-LNPs designed for the delivery of mRNA to the lungs could rescue mice from ALI by delivering IL-22 mRNA (Zhao et al., 2024).

The permeability of the alveolar–capillary barrier increases during ALI, leading to an increase in the width of the vascular–endothelial cell gap. Nanomaterials are therefore able to passively accumulate in the alveolar region of this highly permeable area and thus achieve a passive targeting effect via the enhanced permeability and retention (EPR) effect (Figure 4) (Zhang S. et al., 2024). Wang et al. prepared a drug delivery platform based on triangular DNA origami modified with R9 peptide and demonstrated the ability of this nanomaterial to exert an enhanced passive macrophage-targeting effect in a mouse model of ALI (Wang H. et al., 2024). At the onset of ALI, various biomarkers can be more highly expressed on the surface of endothelial cells, including endothelin-1, L-selectin, E-selectin, and P-selectin (Mokra and Kosutova, 2015; Vassiliou et al., 2020). Nanomaterials are capable of targeting these biomarkers that exhibit increased expression and can thus achieve active targeting by ligand-receptor interactions. Li et al. developed a lung-targeted drug delivery system that targeted intercellular adhesion molecule (ICAM)-1 and delivered simvastatin for the treatment of ALI (Figure 4). This system exhibited good lung-targeting properties in mice with lipopolysaccharide (LPS)-induced ALI and was effective in inhibiting the expression of TNF-α and IL-6 and the infiltration of inflammatory cells. This nano-delivery system was shown to significantly improve the histological condition by hematoxylin-eosin staining, which demonstrated that the nanomaterial can treat ALI via this active targeting mechanism mediated by ICAM-1 recognition (Li et al., 2017). A team designed lung-targeted DEX-loaded nanostructured lipid carriers with the same target. These nanocarriers, which were modified with anti-ICAM-1 antibody, were demonstrated to significantly reduce the infiltration of inflammatory cells in the lung and the production of the proinflammatory cytokines TNF-α and IL-6. They also improved the histological condition in a mouse model of LPS-induced ALI (Li et al., 2018). Furthermore, biomimetic strategies have emerged, such as Cell-derived biomimetic nanoparticle. They have characteristics such as low immunogenicity, long circulation time, and strong targeting. Gao et al. conducted a detailed analysis of the current research progress on cell membrane-based biomimetic technology and extracellular vesicle (EV)-based biomimetic nanotechnology in acute lung injury (ALI), and explored their clinical feasibility. Clinical trials involving EVs are currently underway, indicating that biomimetic nanoparticles offer a promising platform for the treatment of ALI (Gao et al., 2024). Another innovative approach utilizes mesenchymal stem cells and their derived exosomes as nanoparticles that can convey most of the biological effects and therapeutic benefits of their source cells, demonstrating high compatibility with damaged lung tissue and targeted accumulation (Zhu et al., 2013). Moreover, responsive targeting systems, including ROS-responsive polymers and pH-sensitive micelles, have allowed for drug release to be selectively triggered in the inflammatory microenvironment. Zhai et al. developed ROS-responsive polysulfone nanoparticles loaded with dexamethasone (PTKNPs@Dex), demonstrating that PTKNPs@Dex can accumulate at sites of pulmonary inflammation and rapidly release the encapsulated payloads, exerting a responsive targeted effect in the treatment of ALI (Zhai et al., 2022).

Lipid nanocarriers are mainly amphiphilic or hydrophobic molecules composed of phospholipids, cholesterol, fat-soluble drugs, and other auxiliary lipids (Figure 1) (Gordillo-Galeano and Mora-Huertas, 2018). Owing to their simple processing, high biocompatibility, high bioavailability, etc. (Sercombe et al., 2015; Fonseca-Santos et al., 2015; Mitchell et al., 2020), they make efficient drug delivery systems available. The main types of Lipid nanoparticle (LNPs) include liposomes, solid lipid carriers, nanostructured lipid carriers, and nanoemulsions. Bian et al. summarized the characteristics of various lipid nanomaterials used for the treatment of ALI. These included 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) used for the preparation of drug formulations containing DEX and α-tocopherol/glutathione and other lipid components used for the preparation of different medications, e.g., cholesterol, soybean lecithin, and distearoylphosphatidylethanolamine-polyethylene glycol (PEG) (Figure 5A) (Suntres and Shek, 2000; Suntres and Shek, 1996; Hettiarachchi et al., 2019; Chen et al., 2013). The efficacy of LNPs in the treatment of ALI was demonstrated by determining their effects on lung weight, the lung index, and levels of proinflammatory cytokines (e.g., TNF-α, IL-1β, and IL-6), neutrophil elastase, and myeloperoxidase (MPO) and assessing their therapeutic effects in different mouse models (Bian et al., 2021b). Ravivi et al. similarly developed liposomes with DPPC as the main lipid and with sizes of 100 nm for pulmonary drug delivery for the treatment of ARDS. The loading efficiency of drugs in these liposomes reached 98% for methylprednisolone (a steroid) and 92% for NAC (a mucolytic agent). In cell experiments, a reduction in secretion of TNF-α and NO was observed in LPS-stimulated RAW 264.7 macrophages treated with the liposomes. In C57BL/6 mice used as a model of LPS-induced lung inflammation, the therapeutic efficacy of the liposomes in reducing inflammation and secretion of the cytokines TNF-α, IL-6, and IL-1β was observed to be better than that of the free drug administered by the intravenous and endotracheal routes (Figure 5B) (Arber Raviv et al., 2022). Inhalable nanomedicine delivery systems encapsulate drugs within nanoscale carriers and deliver them via inhalation to specific regions or areas of the lungs, particularly those with affected or diseased cells (Kuzmov and Minko, 2015). Compared to traditional treatment methods, inhalable nanomedicine delivery systems can penetrate the mucus barrier, deposit precisely at lung lesion sites, prolong drug retention time, and reduce administration efficiency. Currently, this delivery system is widely used in the treatment of lung cancer, chronic obstructive pulmonary disease, asthma, and other diseases (Jin Z. et al., 2023; Gupta et al., 2022; Anderson et al., 2020; Goswami et al., 2025). Liu et al. developed an inhalable nanoplatform for sequential drug release referred to as D-SEL. This was formed by attachment of a peptide cleavable by matrix metalloproteinase-9 to serum exosomes and liposomes and subsequent encapsulation of methylprednisolone sodium succinate (MPS) (Figure 5C). It was found that treatment with MPS/D-SEL significantly inhibited activation of neutrophils and macrophages, reduced the number of neutrophils, and promoted the polarization of M2-type macrophages in a mouse model of LPS-induced ALI. It also effectively inhibited the expression of proinflammatory cytokines (TNF-α, IL-1β, and IL-6), increased the level of production of anti-inflammatory cytokines (IL-4 and IL-10), and alleviated pathological disorders in the lungs (Figure 5D) (Liu et al., 2023).

Polymeric nanocarrier systems are constructed from natural or synthetic polymers formed from either monomeric units or pre-existing polymers (Figure 1). Various synthesis techniques are available for creating polymeric nanomaterials, including emulsification (via solvent displacement or diffusion), nanoprecipitation, ionic gelation, and microfluidic methods (Kurd et al., 2019; Sawasdee et al., 2018). Polymeric nanomaterials can efficiently carry hydrophobic and hydrophilic drug molecules as a result of their flexible drug delivery capabilities. Consequently, they are extensively employed in domains such as pharmaceutical delivery and genetic delivery. Among these nanomaterials, poly (lactic-co-glycolic) acid (PLGA)-based polymer NPs have been proven to exhibit good drug release tunability, which is a popular area for polymer NPs in terms of research and applications (Jha and Mayanovic, 2023). Recent studies have found that PLGA-mediated stimulation of aging signaling triggers precise macrophage-mediated clearance of inflammatory neutrophils, which can ultimately have the effect of reducing inflammation. Chen et al. developed PC@PLGA polymeric nanoparticles by encapsulating PLGA with platelet-derived vesicle membranes (P) and calmodulin-expressing membranes (C), enabling specific targeting of activated neutrophils and deceiving macrophages into recognizing them as “aging” neutrophils. In an LPS-induced ALI mouse model, these nanoparticles effectively targeted activated neutrophils promoted macrophage-mediated programmed cell removal, and reduced inflammation and tissue damage (Chen et al., 2023). In addition, dendritic macromolecules, with their large internal cavities and dense surface active functional groups, are able to improve bioavailability and biocompatibility and have been studied extensively in ALI (Nikzamir et al., 2021; Albr et al., 2008). Polyamide-amine (PAMAM) dendrimer is one of the most intensively studied dendrimers. Fifth-generation (G5) PAMAM dendrimer was used as the basic platform, which was modified with DEX and PEG on its surface, and gold nanoparticles (GNPs) were encapsulated in the internal cavity to form a nanocarrier with the composition (Au⁰)₂₅-G5NH₂-(PEG-DEX) (denoted by V2). The nanocarrier was then electrostatically bound to a microRNA-155 inhibitor of an anti-inflammatory gene (miR-155i) to form a nanocomplex (V2/miR-155i) (Figure 6A). In vitro studies with mouse alveolar macrophages showed that the nanocomplex exhibited low cytotoxicity and efficiently co-delivered miR-155i and DEX, suppressing TNF-α, IL-1β, and IL-6 mRNA expression (Figure 6C). In an LPS-induced ALI mouse model, airway nebulization of the nanocomplex significantly inhibited proinflammatory factors and improved lung repair, outperforming single-modality chemotherapy and gene therapy, as confirmed by histopathological analysis (Figure 6B) (Li et al., 2021).

Inorganic nanomaterials have been widely studied due to their stable structures, high drug loading rates, and easy surface modification (Figure 1) (Cho et al., 2010). Studies have shown that these materials hold significant potential in the treatment of ALI (Bian et al., 2021b). GNPs, which are a popular subject of research, have been shown to alleviate ALI by inhibiting inflammatory signaling pathways and scavenging ROS (dos Santos Haupenthal et al., 2020). The cumulative toxicity exhibited in vivo, stemming from their prolonged retention within the liver and spleen, coupled with their inherently poor biocompatibility, presents challenges that necessitate further research. Consequently, inorganic peptides have been employed for the modification of GNPs, which has enhanced their biocompatibility and alleviated their associated toxic side effects (Singh et al., 2018). Gao et al. designed a unique class of peptide-GNP hybrids that act as potent nano-inhibitors of TLR4 signaling by modulating the endosomal acidification process. It was found that the size of the NPs was a significant factor in their inhibitory effect on TLR4 (Figure 7B). In particular, a peptide-GNP hybrid with a 20 nm GNP core (P12 (G20)) exhibited the strongest inhibitory activity in THP-1 cell-derived macrophages (Figure 7A). In a mouse model of LPS-induced ALI, P12 (G20) was more effective than P12 (G13) (with a 13 nm GNP core) in prolonging survival time, reducing lung inflammation, and alleviating alveolar injury (Gao et al., 2019). Molybdenum NPs are also promising for scavenging ROS, according to new research findings. Yan et al. developed a functional nanomaterial, namely, molybdenum nanodots (MNDs), with a size of approximately 5 nm by ultrasonic stripping. Their ability to scavenge ROS was assessed by assaying cellular activity in RAW 264.7 cells (a mouse macrophage cell line) and MLE-12 cells (a mouse lung epithelial cell line). It was found that MNDs were able to induce a significant increase in the activity of RAW 264.7 and MLE-12 cells. Intracellular ROS levels were found to be significantly reduced after fluorescence staining. This demonstrated that MNDs were able to limit oxidative-stress-induced damage to RAW 264.7 and MLE-12 cells by scavenging ROS. In a mouse model of LPS-induced ALI, after injection by tracheal drip of different doses of MNDs, bronchoalveolar lavage fluid (BALF) and lung tissues were taken. The levels of ROS in the lung tissues of the mice were determined by dihydroethidium staining, which revealed that the levels of ROS in the lung tissues of mice treated with MNDs were significantly reduced. In addition, it was found that MNDs reduced MPO levels in BALF and decreased the numbers of monocytes/macrophages and neutrophils in lung tissue. Lung histopathological examination showed that MNDs were able to reduce lung tissue injury, which proved that MNDs can exert anti-inflammatory and antioxidant effects and thus reduce ALI (Yan et al., 2023).

Polyphenols are a class of plant-derived antioxidants that are structurally based on the benzene ring and are found in everyday human foods in the form of glycosides or glycosidic elements.

Flavonoids are a class of natural substances widely found in nature, with 2-phenylchromone as the parent structure, usually in the form of free glycosides or combined with sugar to form glycosides, with a wide range of biological activities and pharmacological effects.

Alkaloids are a class of nitrogen-containing alkaline organic compounds that are widely found in plants and have a variety of biological activities such as antimicrobial, anti-inflammatory, antioxidant, antiviral, immunomodulatory and analgesic.

Terpenoids are a class of organic compounds formed by the polymerization of isoprene units (C5H8) that are rich in chemical and biological activities such as anti-inflammatory, anti-cancer and neuroprotective effects (Zhao et al., 2022).

Glycosides are natural products synthesized from a variety of natural plants, with anti-inflammatory, anti-tumor, antioxidant and other effects.

Triterpenoids are terpenoids with a basic nucleus consisting of 30 carbon atoms that have a wide range of biological activities including anti-inflammatory, antioxidant, antitumor and antifibrotic.

Coumarins are a group of secondary metabolites widely found in plants with different biological activities such as anti-inflammatory, antiviral and bacteriostatic effects using phenanthrene α-pyrone as the parent nucleus.