Chemically grafted PEGylation mitigates opsonin adsorption and enhances tumor targeting of MMP-9-responsive nanoparticles

PEGylation strategy determines protein corona composition on nanoparticles. • Surface heterogeneity leads to distinct corona-mediated cellular interactions. • Protein corona differentially affects and macrophage uptake tumor targeting. • Surface-dependent corona formation alters in vivo therapeutic efficacy. Active-targeting nanocarriers are promising for precision cancer therapy, but protein corona formation upon blood contact masks targeting ligands and triggers rapid clearance. Here, we investigate how PEG surface architecture (chemical grafting vs. physical coating) modulates protein corona formation and therapeutic outcomes. Using a star-shaped polymer (PET-PCL) functionalized with an MMP-9-targeted and responsive dual-functional peptide, we engineered two types of NPs with similar bulk properties but different surface poly (ethylene glycol) (PEG) configurations: chemical grafting versus physical coating. Quantitative proteomic analyses revealed that serum incubation led to markedly different protein corona profiles. Notably, chemically grafted NPs exhibited significantly lower adsorption of corona, effectively mitigating opsonin-mediated clearance and preserving targeting functionality. Consequently, these corona-coated NPs demonstrated superior cellular internalization in lung cancer cells (A549) and reduced phagocytosis by macrophages (RAW264.7) compared to their physically coated counterparts. Furthermore, in vivo biodistribution studies in A549 tumor-bearing mice confirmed that chemically grafted NPs achieved enhanced tumor accumulation, which corresponded with favorable antitumor activity. Collectively, these findings elucidate the critical role of surface PEG architecture in regulating protein corona formation and demonstrate that tailored surface engineering can harmonize stealth and targeting functionalities. This work provides a rational design strategy for next-generation targeted nanomedicines aimed at overcoming biological barriers in complex physiological environments. Download: Download high-res image (227KB) Download: Download full-size image