Complement C3 in the silica nanoparticles protein corona promotes macrophage M1 polarization and subacute pulmonary fibrotic remodeling

Silica nanoparticles (SiNPs), widely used in diverse industrial and biomedical applications, are ubiquitous environmental pollutants of emerging concern, posing significant risks to human respiratory health via inhalation exposure. Substantial evidence demonstrates that inhaled SiNPs induce pulmonary fibrosis. Nevertheless, the underlying pathogenic mechanisms remain elusive. While nanomaterials adsorb proteins to form a protein corona that alters their biological activity and contributes to nanoparticle-induced tissue damage, whether this process contributes to SiNPs-induced pulmonary fibrosis remains incompletely characterized. We demonstrated that SiNPs exposure promoted subacute pulmonary fibrotic remodeling and induced macrophage M1 polarization in mice. In vitro, SiNPs formed a protein corona with mouse bronchoalveolar lavage fluid (BALF). The SiNPs protein corona promoted RAW264.7 cells toward M1 phenotype. Integrated proteomic profiling of isolated coronas by LC-MS and human pulmonary fibrosis transcriptomes identified complement C3 as a key corona protein that promoted macrophage M1 polarization and contributed to subacute pulmonary fibrosis progression among the isolated coronas. Mechanistically, the SiNPs-C3 corona enhanced CD86 and MHC-II expression in RAW264.7 cells via the NLRP3/TNF-α/IL-1β axis and directly activated fibroblasts. Pharmacologic blockade of complement C3 with the peptidic inhibitor Cp40 attenuated complement C3 activation, macrophage M1 polarization, and pulmonary fibrosis. Collectively, these findings revealed that complement C3 as a key corona component contributed to SiNPs-induced subacute pulmonary fibrotic remodeling. Complement C3 represented a potential therapeutic target for SiNPs-induced subacute pulmonary fibrosis, providing a rationale for future immunomodulatory therapies.