Codelivery of Shikonin and siTGF-β for enhanced triple negative breast cancer chemo-immunotherapy

Although chemoimmunotherapy has achieved considerable success in cancer treatment in recent years, the cure for triple-negative breast cancer (TNBC) remains elusive. The unsatisfied outcomes are likely attributed to deficient tumor immunogenicity, a strong immunosuppressive tumor microenvironment (ITM) and tumor metastasis. To address this issue, we constructed an effective codelivery system, combined with tumor growth factor beta (TGF-beta) small interference RNA (siTGF-beta) and shikonin (SK), to achieve successful chemoimmunotherapy of TNBC. The SK/siTGF-beta NPs (approximately 110 nm) exhibited a uniform structure and good stability. Conjugated FA presented enhanced cellular uptake in 4T1 cells, and siTGF-beta escaped from lysosomes because of the proton sponge effect of PEI. Furthermore, SK actually induced satisfactory immunogenic cell death (ICD) and the resulting dendritic cell (DC) maturation facilitated a distinctly enhanced cytotoxic T lymphocyte (CTL) response, generating a positive effect on tumor suppression. Simultaneously, the successful silencing of TGF-beta alleviated the TGF-beta-mediated ITM and inhibited the epithelial-to-mesenchymal transition (EMT), contributing to the infiltration of CTLs, suppression of regulatory T lymphocyte (Treg) proliferation and lung metastasis inhibition. Thus, the SK/siTGF-beta NPs demonstrated the strongest therapeutic effect with delayed tumor growth (TIR = 88.5%) and lung metastasis restraint (77.3%). More importantly, tumor rechallenge assay suggested that the codelivery system produced a long-term immunological memory response to prevent tumor recurrence. Based on boosting the immune response and combating the ITM, SK/siTGF-beta NPs would be a potential approach for TNBC therapy.

Automated summary

By constructing an effective codelivery system combining tumor growth factor beta (TGF-beta) small interference RNA (siTGF-beta) and shikonin (SK), this study achieved successful chemoimmunotherapy of triple-negative breast cancer (TNBC), inhibiting tumor growth and metastasis while generating long-term immunological memory response.