Radiation-induced pulmonary fibrosis (RIPF) is the most serious complication associated with radiotherapy in case of thoracic tumors, as it severely threatens the life safety of patients [1]. A cohort study reported that a follow-up observation of breast cancer patients after radiotherapy yielded a cumulative incidence of pulmonary fibrosis of 9.95% at 2 years, which was much higher than that of other side effects [2].

According to studies, the development process of pulmonary fibrosis is progressive and irreversible. It is primarily manifested in the destruction of alveolar structure through collagen deposition and scar formation, eventually leading to organ dysfunction, interruption of gas exchange, respiratory failure, and death [3]. Despite several studies on the pathogenesis of pulmonary fibrosis, the underlying mechanisms remain largely unknown [4], [5]. Several cells, including fibroblast, and alveolar epithelial cells, are involved in the occurrence and development of pulmonary fibrosis; however, it is widely believed that immune response is the key factor influencing fibrosis [6], [7]. Therefore, macrophages have received increasing attention in this context. The immune response is initiated by oxidative stress after the lungs are damaged, and macrophages are recruited and activated [8], [9], [10]. Macrophages with pro-inflammatory phenotype (M1) have been found to dominate the pro-inflammatory phase of lung injury, based on the involvement of nitric oxide synthase (iNOS), tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and other factors that clear necrotic cells and damaged tissue, and initiate tissue repair. Macrophages with anti-inflammatory phenotype (M2) dominantly occur during tissue repair/regeneration, expressing high levels of arginase 1 (ARG1), transforming growth factor β1 (TGF-β1), and interleukin 10 (IL-10) to suppress inflammatory responses. However, if the balance between the two phenotype is disturbed and M2 macrophages are continuously activated, proliferation, differentiation, and activation of fibroblasts, epithelial cells, endothelial cells, stem and progenitor cells proliferation are stimulated. This result in, chronic inflammation, which further leads to pathological fibrosis [11], [12].

Currently, owing to the irreversibility and refractory nature of pulmonary fibrosis, its clinical treatment mainly focused on supportive and symptomatic therapy. Till date, only two drugs, nintedanib and pirfenidone, have been approved by the FDA for the treatment of idiopathic pulmonary fibrosis (IPF). However, they have limited efficacy and are associated with various adverse side effects, including gastrointestinal nausea and vomiting [13], [14], and even fatal events such as acute exacerbations [15], [16]. Moreover, there is no evidence proving its efficacy for RIPF. Furthermore, owing to the first-pass metabolism of the liver and poor targeting to the lung, these drugs unable to effectively reach and accumulate within lungs, which renders them less effective when administered either intravenously or orally [17], [18], [19].

Polydopamine nanoparticles (PDA NPs), have been reported that it exhibits great therapeutic potential against pulmonary fibrosis and regulate the expression of M2 macrophages [20], [21]. PDA NPs is a type of multifunctional polymer with melanin-like properties which is synthesized via self-oxidative polymerization of dopamine hydrochloride (DA) under alkaline conditions [22]. Because of its unique and excellent properties, PDA NPs is widely used in various fields, particularly in biomedicine. Owing to its excellent ability to scavenging reactive oxygen species (ROS) and rich functional groups, PDA NPs were modified with other drugs against fibrosis [23], [24].

However, conventional PDA NPs still suffer from some defects, such as insufficient cellular uptake and inefficient macrophages-targeting ability. Studies have indicated that mannose could specially target M2 macrophages ubiquitously expressed mannose receptors [25]. Therefore, this study designed mannosylated polydopamine nanoparticles (MPDA NPs) and use aerosol administration to evaluate the properties of MPDA in mucus penetration, cellular uptake, ROS-scavenging, etc. furthermore, this study explored the its action mechanism and provide a novel strategy for prevention and treatment of RIPF.