Abstract: Current cancer therapy faces three major challenges: 1) difficulty in eradicating cancer stem cells (CSCs), leading to tumor recurrence; 2) poor intracellular delivery of anticancer drugs, resulting in drug resistance; and 3) inability to precisely deliver drugs to tumor sites, causing damage to normal cells. To simultaneously address these issues, an intelligent nano-drug delivery system (DMHCS) based on 3,29-dibenzoylkarounidiol (D), nanoparticulate montmorillonite (M), hyaluronic acid (H), chitosan (C), and sodium alginate (S) was developed. This system leverages the specific CSC-targeting ability of hyaluronic acid, the cell membrane-penetrating capacity of nanoparticles, and the tumor microenvironment-responsive drug release property of the pH-sensitive hydrogel.Experimental results demonstrated that: 1) Montmorillonite was uniformly distributed as nano-sheets within the DMHCS matrix. 2) DMHCS exhibited excellent pH-sensitive drug release, with a release rate in the simulated tumor microenvironment 2.48 times higher than in normal physiological conditions. 3) DMHCS effectively inhibited the proliferation of HGC27 gastric cancer stem cells, with an IC₅₀ value of 52.97 μg/mL. 4) The apoptosis-inducing ability of DMHCS in gastric cancer cells was 1.82 times greater than that of free DBOK. 5) DMHCS showed a potent inhibitory effect on the invasion of gastric cancer cells, which was 3 times stronger than the free drug. 6) DMHCS displayed significantly enhanced targeting and specific killing efficacy against gastric CSCs, with an 8.5-fold improvement.In conclusion, the DMHCS system effectively addresses the three major challenges in cancer therapy, showing great promise and providing novel strategies for the development of new anticancer agents.