Albendazole-loaded γ-cyclodextrin metal-organic frameworks sensitize hepatocellular carcinoma to low-dose doxorubicin via ROS-associated immunogenic cell death.

Doxorubicin (DOX) is widely used to treat hepatocellular carcinoma, but its dose-dependent cardiotoxicity limits its clinical application. Although dose reduction can mitigate cardiac injury, it often weakens antitumor efficacy, underscoring the need for effective sensitization strategies. Albendazole (ABZ) can induce reactive oxygen species (ROS) production, which may promote immunogenic cell death (ICD); however, its poor aqueous solubility restricts therapeutic application. To overcome this limitation, γ-cyclodextrin-based metal-organic frameworks were used to encapsulate ABZ, generating MOF-ABZ for low-dose DOX sensitization. MOF-ABZ improved ABZ dispersion and induced ROS-associated immunogenic responses in HepG2 cells, as indicated by the release of damage-associated molecular patterns (DAMPs), dendritic cell maturation, and early CD8+ T-cell activation; these effects were attenuated by N-acetylcysteine. MOF-ABZ further sensitized HepG2 cells to DOX, reducing the DOX IC₅₀ from 119.5 to 91.3 ng/mL. In H22 tumor-bearing mice, the combination of low-dose DOX and MOF-ABZ achieved tumor inhibition comparable to that of high-dose DOX alone and superior to that of low-dose DOX monotherapy, with less body-weight loss, milder histological myocardial damage, and cytokine changes consistent with immunomodulatory activity. In conclusion, through efficient ABZ delivery, MOF-ABZ enhances the antitumor efficacy of low-dose DOX, and these ROS-associated immunogenic responses potentially contribute to this sensitization effect, providing a promising strategy to improve the therapeutic index of DOX in HCC models.