Nanoparticle-mediated celastrol ER targeting delivery amplify immunogenic cell death in melanoma

Endoplasmic reticulum (ER) stress is essential for activating intracellular signaling pathways of immunogenic cell death (ICD), targeting drugs to ER might improve ICDrelated immunotherapy. In this study, an ER targeting nanoparticle was designed to boost celastrol-induced cancer immunotherapy. The nanoparticle (TSE-CEL/NP) was self-assembled using PLGA loaded with celastrol as a hydrophobic core and ptosylethylenediamine (TSE) modified DSPE-PEG as a surface modified material. After entering tumor cells, nanoparticles utilize the p-tosylethylenediamine (TSE) targeting property to locate the endoplasmic reticulum, and then induce ER stress and boost ICD. Which further promote the recruitment and maturation of DC cells, leading to cytotoxic T lymphocytes (CD8+T cells) proliferation and activation, ultimately improve the immunotherapy efficacy against melanoma. [Display omitted] •An ER targeting nanoparticle (TSE-CEL/NP) was successfully synthesized.•TSE-CEL/NP could specially target to the ER, and induce ER stress and boost immunogenic cell death.•TSE-CEL/NP activates CD8+ T cells and promotes the recruitment and maturation of DC cells in tumor microenvironment. Chemoimmunotherapy, which benefits from the combination of chemotherapy and immunotherapy, has emerged as a promising strategy in cancer treatment. However, effectively inducing a robust immune response remains challenging due to the limited responsiveness across patients. Endoplasmic reticulum (ER) stress is essential for activating intracellular signaling pathways associated with immunogenic cell death (ICD), targeting drugs to ER might enhance ER stress and improve ICD-related immunotherapy. To improve the immune response of Chemoimmunotherapy. ER targeting nanoparticles TSE-CEL/NP were constructed to enhance immunogenic cancer cell death. Flow cytometry, confocal microscope, TEM and immunofluorescence were used to evaluate the ER targeting effect and immunogenic tumor cell death in vitro on B16F10 tumor cells. Unilateral and bilateral tumor models were constructed to investigate the efficacy of anti-tumor and immunotherapy in vivo. Lung metastasis B16F10 melanoma tumor-bearing mice were used to assess the anti-metastasis efficacy. TSE-CEL/NP could specially accumulate in ER, thereby induce ER stress. High ER stress trigger the exposure of CRT, the extracellular release of HMGB1 and ATP. These danger signals subsequently promote the recruitment and maturation of dendritic cells (DCs), which in tur