<p>Astragaloside (AST) has shown therapeutic potential against non-small cell lung cancer (NSCLC). However, its poor water solubility and low bioavailability limit its clinical application. To overcome these challenges, we developed an AST-loaded zeolitic imidazolate framework-8 (AST@ZIF) using supercritical fluid carbon dioxide (SCF-CO₂) technology. This approach aimed to enhance the solubility, bioavailability, and anti-tumor efficacy of AST. Notably, this is the first study to employ SCF-CO₂ as an anti-solvent through solution-enhanced dispersion by supercritical fluids (SEDS) for preparing drug-loaded ZIF-8. The resulting AST@ZIF-SEDS displayed a uniform hexagonal or cubic morphology, with AST transitioning from a crystalline to an amorphous state. Compared to AST@ZIF prepared using traditional methods (one-pot synthesis and solvent adsorption), AST@ZIF-SEDS demonstrated superior drug loading capacity, dispersibility, reduced residual solvent content, and improved stability. As a novel carrier, ZIF-8 effectively enhanced the solubility and bioavailability of AST while maintaining favorable biosecurity. In vivo studies further confirmed that AST@ZIF-SEDS significantly improved tumor inhibition compared with AST powder. In conclusion, SEDS technology represents a promising strategy for maximizing the therapeutic potential of ZIF-8 as a drug carrier. AST@ZIF-SEDS exhibited strong anti-tumor activity and holds potential as an effective treatment for NSCLC.</p> Graphical abstract <p></p>