Biomimetic polydopamine nanoassembly regulates M2 macrophage polarization to alleviate radiation-induced pulmonary fibrosis via the PI3K/AKT/S100A4 pathway

• The pH-responsive HMPDA enhance niclosamide release. • Coating of macrophage membrane target injured lung. • The nanoassembly alleviate radiation-induced pulmonary fibrosis . • The nanoassembly regulate M2 macrophage polarization via PI3K/AKT/S100A4 pathway. Radiation-induced pulmonary fibrosis (RIPF) is a severe and life-threatening complication that often occurs following radiotherapy for thoracic tumors or accidental nuclear exposure. Once lung fibrosis develops, it is challenging to reverse, making early prevention crucial. Additionally, the low targeting efficiency of drugs for lung diseases significantly limits their therapeutic effectiveness. In this study, we designed a pH-responsive and inflammation-targeted biomimetic polydopamine nanoassembly, NCL-HMPDA@CM (NHC). This nanoassembly consists of hollow mesoporous polydopamine nanoparticles (HMPDA) loaded with niclosamide (NCL), which can effectively inhibit M2 macrophage polarization, then further modified with lung macrophage membrane to enhance lung-targeting capabilities. Both in vivo and in vitro experiments demonstrate that NHC achieves significant lung targeting, improves lung function, and reduces the expression of Col1a1, α-SMA, and TGF-β. Moreover, mRNA sequencing and flow cytometry reveal that NHC effectively regulates M2 macrophage polarization by blocking the PI3K/AKT/mTOR pathway and further inhibiting the S100A4/PPARγ signaling pathway. This study presents a promising strategy for the prevention and treatment of RIPF.