The fibrosis-targeting “Swiss Army Knife”: a biomimetic nanomotor reversing pulmonary fibrosis via dual-pathway immunometabolic reprogramming

In the realm of medical research, it is widely recognized that idiopathic pulmonary fibrosis (IPF) constitutes a distinct subtype of interstitial lung disease (ILD). Its progression appears to be relentless, and it can be life-threatening. Moreover, the available treatment options for this condition are rather restricted in range, and to a certain degree, they mainly serve a palliative purpose. Dysregulated lipid metabolism and hyperactivation of the cGAS–STING signaling pathway are established key drivers of fibrotic progression. To address these pathological mechanisms, we developed a multifunctional nanomotor, PMPDA@HDL, consisting of HDL-loaded polydopamine nanoparticles camouflaged with a macrophage membrane functionalized with a collagen I-targeting peptide, where HDL represents the combined payload of H-151, DHA, and L-arginine. Upon NIR irradiation, L-arginine-derived NO enables nanomotor propulsion. The resulting nanomotors (∼300 nm) The nanoparticles exhibited excellent colloidal stability. Additionally, it demonstrated a reasonable and quantifiable level of biocompatibility. Moreover, when exposed to 808 nm near-infrared radiation, it showed a potentially potent and efficient photothermal reaction. This property enhances tissue penetration and the controlled drug release process. In vitro, PMPDA@HDL selectively bound to collagen-rich extracellular matrices, suppressing fibroblast activation, matrix contraction, and senescence phenotypes. In a bleomycin-induced murine IPF model, PMPDA@HDL accumulated preferentially in fibrotic lung tissue, significantly reducing collagen deposition, downregulating pro-inflammatory and pro-fibrotic mediators, and improving pulmonary function. Integrated RNA sequencing and mechanistic studies revealed that PMPDA@HDL orchestrates dual-pathway reprogramming, concurrently inhibiting the cGAS–STING–mediated senescence-associated secretory phenotype (SASP) and activating the KEAP1–NFE2L2 antioxidant pathway, thereby synergistically restoring immunometabolic homeostasis. Together, this collagen-anchored, macrophage-membrane-biomimetic nanomotor represents a potent, targeted nanotherapeutic strategy for multi-mechanistic intervention in IPF.