Apoptotic body-encapsulated zinc-doped Salvia miltiorrhiza carbon dots trigger PANoptosis for targeted therapy of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) stands as one of the most lethal cancers globally, with its treatment constrained by limitations of conventional therapies. In this study, we developed zinc-doped <i>Salvia miltiorrhiza</i>-derived carbon dots (Zn-SaCDs) and encapsulated them within apoptotic bodies (Zn-SaCDs@Ap) to induce targeted, broad-spectrum cell death in hepatocellular carcinoma (HCC). In vitro experiments reveal that Zn-SaCDs@Ap effectively inhibits stemness properties and invasive potential while triggering robust apoptosis in HCC cells. Furthermore, studies on orthotopic liver tumors and subcutaneous tumors in mice showed that Zn-SaCDs@Ap can effectively inhibit tumor growth. It is noteworthy that Zn-SaCDs@Ap can induce various types of cell death, including apoptosis, pyroptosis, and necroptosis. Transcriptome analysis reveals that Zn-SaCDs@Ap treatment markedly activates the expression of the C2H2 zinc finger family transcription factors (KLF7, SALL4, SNAI2, ZNF516), which enhance the expression of key proteins involved in PANoptosis regulation, such as AIM2 and NAIP. In conclusion, Zn-SaCDs@Ap can inhibit the progression of HCC though inducing PANoptosis of tumor cells. Zn-SaCDs@Ap demonstrates potential as a novel therapeutic agent for hepatocellular carcinoma (HCC).