Personalized Pathogenic Nanoplastic Coronas Orchestrate Efferocytosis-Driven Immune Evasion in Lung Adenocarcinoma.

Abstract

Airborne nanoplastic (NP) pollution is an emerging threat to respiratory health. Although inhaled NPs rapidly acquire a protein corona that shapes their bioactivity, the consequences of this process in cancer-susceptible lungs remain unclear. Here, we investigated whether NPs form a disease-specific pathogenic protein corona in lung adenocarcinoma that rewires immune signaling and accelerates tumor progression. Polyethylene terephthalate (PET) NPs were generated by mechanical fragmentation and extensively characterized. In tumor-bearing mice, inhaled PET NPs accelerated tumor growth relative to controls. Proteomic analysis of PET NPs incubated with bronchoalveolar lavage fluid from patients with lung adenocarcinoma identified lysozyme (LYZ) as a selectively enriched corona component associated with tumor stage and metastasis. Corona formation induced conformational remodeling of LYZ, enhanced its enzymatic activity, and prolonged its membrane retention. Mechanistically, corona-bound LYZ engaged Toll-like receptor 4 and activated a PGRN-LXRα signaling axis, thereby increasing lysosomal acidification-dependent efferocytosis, promoting M2 macrophage polarization, and reducing CD8⁺ T-cell infiltration. <i>In vivo</i>, AAV9-mediated knockdown of <i>LYZ</i> or <i>PGRN</i> attenuated PET NP-induced efferocytosis, reversed immunosuppressive reprogramming, restored CD8⁺ T-cell infiltration, and suppressed tumor growth, demonstrating the functional requirement for this corona pathway. These findings establish disease-derived PET NP coronas as active nano-bio interfaces that connect environmental PET NP exposure with efferocytosis-driven immune evasion in lung adenocarcinoma. This work provides a mechanistic link between airborne NPs and tumor progression in susceptible hosts and highlights corona-mediated signaling as a potential therapeutic target and environmental health concern.