Targeted metabolic reprogramming with lactate-scavenging CeO2@PLP nanoparticles attenuates pulmonary fibrosis via dual modulation of macrophage polarization and fibroblast activation

• First demonstration that PS-PEG enables fibrotic lung targeted delivery via interaction with TREM2. • First demonstration that LA elimination could been explored as a therapeutic approach for IPF. • First demonstration that CeO 2 @PLP prevent IPF by synergistically degradation of LA via LOx, ROS scavenging through CeO 2 and anti-fibrosis by PFD. Idiopathic pulmonary fibrosis (IPF) represents a devastating age-related pulmonary disorder characterized by high mortality and limited treatment options. Emerging evidence implicates pathological lactate (LA) accumulation as an important driver of fibroblast activation and M2 macrophage polarization in IPF progression, yet no existing therapies directly target LA elimination. This study develops an innovative therapeutic approach using phosphatidylserine-conjugated polyethylene glycol (PS-PEG)-coated, hollow mesoporous CeO 2 nanoparticles co-loaded with lactate oxidase (LOx) and pirfenidone (PFD) (CeO 2 @PLP). The nanoplatform demonstrates triggering receptor expressed on myeloid cells 2 (TREM2)-mediated targeted delivery to fibrotic lungs, coupled with pH-responsive payload release. CeO 2 @PLP simultaneously addresses multiple pathological mechanisms: LOx-mediated LA degradation, CeO 2 -derived ROS scavenging through SOD/catalase-mimetic activity, and PFD’s anti-fibrotic action. This multifaceted intervention effectively reduces excess LA in fibrotic microenvironments while inhibiting LA-induced M2 macrophage polarization and fibroblast differentiation. In bleomycin-induced pulmonary fibrosis models, CeO 2 @PLP synergistically improves pulmonary function, attenuates extracellular matrix overproduction, and alleviates lung fibrosis without significant adverse effects. The study not only establishes LA elimination as a viable therapeutic strategy for IPF but also provides a robust nanomedicine platform with potential applications in other LA-associated diseases, representing a significant advancement in targeted metabolic therapy for fibrotic disorders.