Objective To prepare a self-assembled nanoparticles of saikosaponin D (SSD) and cannabidiol (CBD) and preliminarily investigate their anti-hepatoma mechanism in vitro. Methods The SSD-CBD self-assembled nanoparticles were constructed using the nano co-precipitation method at a mass ratio of 3∶1, and their assembly mechanisms were characterized by techniques including X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR), and ¹H-¹H nuclear overhauser enhancement spectroscopy (¹H-¹H NOESY). Its physicochemical properties were evaluated by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The antitumor activity, apoptosis induction, and preliminary mechanisms were systematically assessed by MTT assay, flow cytometry (Annexin V-FITC/PI staining), and cysteinyl aspartate specific proteinase (Caspase) activity assays. Results The assembly was self-assembled through hydrogen bonding and hydrophobic interactions, with SSD and CBD showing a synergistic effect against HepG2 cells (CI = 0.79). It exhibited pH-responsive drug release, specifically releasing drugs in the tumor microenvironment (pH 6.8) while remaining stable at normal physiological environment (pH 7.4). Mechanistic studies indicated that it primarily induced HepG2 cell death by activating the mitochondrial apoptotic pathway. Conclusion The constructed SSD-CBD self-assembled nanoparticles offer a carrier-free strategy that can simultaneously improve the delivery efficiency of CBD and achieve precise collaborative drug delivery, providing an experimental basis for the development of intelligent nanomedicine based on SSD.

saikosaponin D  /  cannabidiol  /  apoptosis  /  self-assembled nanoparticles  /  cytopharmacology