Radiation-induced pulmonary fibrosis is a chronic interstitial lung disease caused by ionizing radiation, which has seen an increase in incidence along with the rise in cancer rates and the use of radiotherapy [1]. Additionally, the continued reliance on nuclear power has led to the proliferation of nuclear plants globally, increasing the risk of radiation-related incidents [2]. Currently, there are limited pharmacological options available for the prevention and treatment [3] of radiation-induced pulmonary fibrosis, in contrast, the risk of this disease is high for it is a major complication associated with various medical interventions such as total body irradiation for hematopoietic stem cell transplantation, nuclear accidents, and thoracic radiotherapy for lung cancer, breast cancer, thymoma, and lymphoma [4]. Therefore, it is crucial to identify effective drugs for the management of this condition.

Inflammation plays a crucial role in the pathogenesis of radiation-induced pulmonary fibrosis. The ionizing radiation generates superoxide free radicals that directly damage the lung's epithelial or endothelial cells. This initial lung injury leads to an influx of activated inflammatory cells into the lung parenchyma. The cytokines produced by these inflammatory cells promote pulmonary fibrosis by stimulating collagen accumulation and epithelial mesenchymal transformation [5,6]. It has been reported the transformation of Monocyte into M2 macrophages plays an important role in the process of pulmonary fibrosis, as it improves fibrosis, which indicates that inhibiting M2 cells can be a potential therapeutic target for RIPF [7,8].

Rosmarinic acid (RA) is a polyphenolic hydroxyl acid known for its anti-inflammatory effects [9]. Recent studies have shown that RA can induce apoptosis in lung fibroblasts [10], and inhibit radiation-induced pulmonary fibrosis by preventing inflammation and inhibiting the RhoA/Rock pathway [11]. Previous research has primarily administered RA prior to radiation exposure to provide protection and continued its administration after irradiation. However, this approach does not offer long-term protective effects. To address this, a treatment strategy focused on extending the retention time of RA in the body, particularly in the lungs, needs to be explored. This necessitates the study of an efficient or long-acting or sustained-release drug delivery system.

The research on passive targeting of the lungs using microspheres is relatively mature, and related studies can be traced back to the 1960s [12,13]. The lung is the only organ in the body that receives all venous blood output from the heart and intravenous injection of microspheres larger than the diameter of pulmonary capillaries can trap them in the pulmonary capillary system. Microspheres are embedded in capillaries, not small arteries, causing blockage of capillaries. At this time, unused capillaries are recruited, and the lungs continue to function normally instead of occurring pulmonary embolism [14,15]. When using microspheres for passive targeting, it is necessary to ensure normal pulmonary microvascular hemodynamics and avoid acute massive embolism caused by vascular occlusion. Therefore, controlling the size of microspheres is important [16]. At the same time, microspheres must be biodegradable in order to promote their elimination after drug release and avoid the accumulation of polymers/delivery carriers in the body [17]. Therefore, it is crucial to develop microspheres using non-toxic and non-immunogenic materials.

Poly (lactic-co-glycolic acid) (PLGA) is a copolymer with excellent biodegradability, biocompatibility, sustainable release, targeted drug delivery, and protection of preparations from degradation. In addition, the hydrolysis of PLGA in the body produces two monomers (lactic acid and glycolic acid), both of which are common cellular metabolites. So, it is a suitable carrier material [18,19]. Previous studies have investigated the use of PLGA microspheres for drug encapsulation and sustained release, with the ability to control microsphere size [[20], [21], [22]]. An ideal carrier system should not only regulate drug release and minimize side effects, but also exhibit lung-targeting capabilities. We designed poly (lactic-co-glycolic acid) (PLGA) microspheres as carriers for rosmarinic acid, and they were administered intravenously to enter the pulmonary circulation. Lung targeting was achieved by carefully controlling the size of the microspheres to ensure they retention in the pulmonary capillaries [16]. In this study, we validate the lung tissue targeting ability of the drug and examine its therapeutic effect on animal models of radiation-induced pulmonary fibrosis (RIPF). Molecular pathological analysis revealed that the drug's mechanism of action involves the regulation of inflammation and macrophage polarization. These findings have significant implications for the prevention and treatment of RIPF.