ERG/DOTAP modulation of Physiological Response to AIE-Visualized Nanoliposomes is dominated by Protein Corona

Lipid nanoparticles (Lips) are studied as drug delivery systems for superior biocompatibility, low toxicity, and high encapsulation efficiency. Their size, charge, and hydrophilicity are tunable via material composition and functional groups for tailored tissue distribution. In biological environments, Lip adsorbs proteins to form a "protein corona (PC)," which alters its physicochemical property and biological interaction. Nevertheless, the mechanisms of PC regulating Lip-tissue targeting remain unclear, with limitations of inaccurate in vivo fluorescence quantification and poor stability. To track Lip fate in vivo, self-synthesized aggregation-induced emission fluorescent nanoparticle (AIEgen R1) was used as a template and encapsulated by Lips with varied material compositions and proportions to prepare visualized nanoliposome R1@Lip. In contrast, using ergosterol (ERG) as membrane material, R1@Lip-4 exhibited fluorescence signals of 55.4% in liver and 13.3% in lung tissue, with stronger liver-targeting than cholesterol (CHOL)-based ones. In vitro uptake validated tissue tropism. Proteomic analysis demonstrated that 8% DOTAP led to an increase in liver-targeting proteins (e.g., TRFE, FIBA), while 30% DOTAP content resulted in the enrichment of lung-targeting proteins such as ANXA1 and PDLI1. Substituting CHOL with ERG led to a reduction in lung-targeting proteins while increasing liver-targeting proteins (e.g., FIBA). This indicated that R1@Lip-4 with 30% cationic exhibited a wider liver distribution than R1@Lip-3. These findings establish an "R1@Lip-PC-tissue targeting" relationship, facilitating precise modulation of PC properties through Lip formulation to enhance tissue targeting.