Impact of protein corona and PEGylation on the accumulation and efficacy of lysosome-disrupting lipid nanoparticles in KRAS-mutated cancer

Nanomedicines offer promising approaches for targeted drug delivery to tumor cells but their clinical translation is hindered by limited delivery efficacy in heterogenous clinical tumors. Protein corona adsorbed to the surface of nanoparticles (NPs) would cause opsonization and accelerate blood clearance, posing a significant barrier to effective drug delivery. Polyethylene glycol (PEG) modification is widely employed to prolong the NPs' circulation time and improve the delivery efficacy. Nevertheless, the clinical efficacy of PEG-based nanomedicines is still debatable. Here, we prepared non-PEGylated lysosomal-disrupting dimeric chloroquine (CQ) lipid nanoparticles (DCLNPs) and PEGylated DCLNPs (PEG-DCLNPs) and systematically studied the impact of PEGylation on DCLNPs' delivery efficacy in KRAS-mutant (MT) and -wildtype (WT) cancers. We found that the protein corona facilitates KRAS-MT cancer-specific targeted delivery of DCLNPs by exploiting extracellular protein engulfment preference. In contrast, PEGylation hindered delivery and efficacy of DCLNPs. Proteomics analysis highlighted apolipoproteins, particular apolipoprotein E, as key factors promoting the uptake of DCLNPs. Additionally, DCLNPs sensitized immunosuppressive KRAS-MT cancers to anti-PD1 immunotherapy. These results underscore the importance of comprehending the context-dependent role of the protein corona in regulating nanoparticle biodistribution, suggesting that PEGylation may not be suitable across all cancer types.