Protein corona formation on supramolecular polymer nanoparticles causes differential endosomal sorting resulting in an attenuated NLRP3 inflammasome activation

Upon introduction into biological environments, nanoparticles undergo the spontaneous formation of a dynamic protein corona, which continually evolves and significantly modifies their physicochemical properties and interactions with biological systems. This evolving protein corona can critically impact the nanoparticles' endocytic pathways and targeting efficiency, potentially altering their functional characteristics and obscuring their intended therapeutic effects. Despite considerable focus on the characterization of corona proteins and their impact on nanoparticle uptake, the intracellular processes and their effects on immunogenicity are not yet thoroughly understood. Supramolecular polymer nanoparticles (SNPs) with a highly hydrophobic core are recognized for triggering NLRP3 inflammasome activation, a key component of the innate immune system. Here, it is reported that the protein corona formation on SNPs exerts an inhibitory effect on the activation pathway of NLRP3 inflammasome. The protein corona impairs the intrinsic capacity of SNPs to induce lysosomal membrane rupture, thereby diminishing the cellular stress signals necessary for the formation of the NLRP3 inflammasome complex. Furthermore, the cells transport SNPs with an attached protein corona to recycling endosomes, where they are sorted and prepared for exocytosis. Conversely, nascent SNPs are primarily confined to late endosomes and lysosomes, leading to lysosomal rupture and inflammasome activation. This differential routing reflects the significant impact of the protein corona on the cellular handling and subsequent biological activity of nanoparticles. In summary, this study elucidates the fundamental role of the protein corona in shaping the intracellular disposition of nanoparticles, with implications for modulating their interactions with the immune system.