Lipoprotein-mimicking nanotherapeutics reconstituted with chenodeoxycholic acid modified protein for efficient tumor targeting

Lipoprotein-derived nanotherapeutics based on endogenous lipid supramolecules have been regarded as an exceptional and promising approach for anti-tumor drug delivery. However, certain challenges associated with the main component apolipoprotein, such as limited availability, high cost, and insufficient specificity of relevant receptor expression, pose significant barriers to its widespread development and application. The objective of this study is to fabricate lipoprotein-mimicking nanocomposites, denoted as CA-P-rHDL by substituting apolipoprotein with chenodeoxycholic acid (CA) modified bovine serum albumin (BSA), and subsequently assess their tumor-targeting capability and anti-tumor efficacy. CA modified BSA (CA-BSA) was successfully synthesized and characterized by quantifying the degree of protein substitution. Subsequently, a nanostructured lipid carrier (NLC) mimicking the hydrophobic core of natural lipoproteins was attached with CA-BSA to form a lipoproteinmimic nanocomplex termed as CA-rHDL. CA-rHDL was endowed with lipoprotein-like structures, favorable particle size, zeta potential and excellent paclitaxel encapsulation (termed as CA-P-rHDL). The internalization of CA-rHDL by HepG2 cells exhibited significantly superior efficiency, with a notably higher in HepG2 cells compared to LO2 cells. Confocal laser scanning microscopy revealed that CA-rHDL evaded lysosomal degradation and was evenly distributed throughout the cells. CCK-8 studies demonstrated that CA-P-rHDL exhibited significantly superior inhibition of tumor cells growth compared to other paclitaxel formulations in vitro. Moreover, in vivo imaging observation in H22 tumor-bearing mouse models exhibited a rapid and consistent accumulation of CA-rHDL within tumors, while CA-P-rHDL demonstrated remarkable efficacy against cancer in these mice. These exceptional capabilities of CA-P-rHDL can be attributed to the synergistic targeting effect facilitated by the combination of CA and BSA, rendering it a promising and versatile drug delivery system for targeted anticancer therapy. Consequently, CA-P-rHDL established a highly potential platform for simulating the reconstitution of supramolecular nanovehicles.