Magnetic field boosted ferroptosis-like cell death and responsive MRI using hybrid vesicles for cancer immunotherapy

Abstract

We report a strategy to boost Fenton reaction triggered by an exogenous circularly polarized magnetic field (MF) to enhance ferroptosis-like cell-death mediated immune response, as well as endow a responsive MRI capability by using a hybrid core-shell vesicles (HCSVs). HCSVs are prepared by loading ascorbic acid (AA) in the core and poly(lactic-co-glycolic acid) shell incorporating iron oxide nanocubes (IONCs). MF triggers the release of AA, resulting in the increase of ferrous ions through the redox reaction between AA and IONCs. A significant tumor suppression is achieved by Fenton reaction-mediated ferroptosis-like cell-death. The oxidative stress induced by the Fenton reaction leads to the exposure of calreticulin on tumor cells, which leads to dendritic cells maturation and the infiltration of cytotoxic T lymphocytes in tumor. Furthermore, the depletion of ferric ions during treatment enables monitoring of the Fe reaction in MRI-R2* signal change. This strategy provides a perspective on ferroptosis-based immunotherapy.

Fig. 1. Exogenous MF-boosted Ferroptosis-like cell death.

a Scheme of exogenous MF-boosted Fenton reaction and responsive magnetic resonance imaging (MRI) using HCSVs, b TEM images of HCSVs treated with the circularly polarized magnetic field (MF, 2 Hz) for various time-periods. Experiments were repeated three times. c Relative concentration change of Ferrous ions tested by the ferrous probe, n = 3 independent samples. Data are shown as means ± s.d. d Ferrostatin-1 rescued TRAMP-C1 cells treated with HCSVs with/without MF, n = 3 independent samples. P = 0.017 e Flow cytometry assay of calreticulin (CRT) exposure on the surface of TRAMP-C1 after various treatment. f Relative quantification of Flow cytometry assay of CRT exposure. n = 3 independent samples. Data are shown as means ± s.d. p < 0.05, two-tailed paired t-test. Source data are provided as a Source data file.

Fig. 2. Responsive MRI.

a In vitro R2* value of IONCs treated with/without AA, R square are 0.9963 and 0.8287 for IONCs (black cure) and IONCs + AA (red curve), respectively. b In vivo R2* change after intra-tumoral injection of HCSVs treated with/without MF. R square are 0.9520 and 0.9741 for red curve (with MF) and blue curve (without MF), respectively. (n = 3 independent samples) Data are shown as means ± s.d. c Related R2* mapping after intra-tumoral injection of HCSVs treated with/without MF (red cycle indicated tumor region). Source data are provided as a Source data file.

Fig. 3. Combination therapy-mediated antitumor effect in a TRAMP-C1 tumor model.

a in vivo treatment timeline. b tumor growth curves of the TRAMP-C1. c the record of mouse weight. d tumor weight at the end time point. (n = 6 independent samples). Data are shown as means ± s.d. e the typical ex vivo photo of dissected tumors from various treatment. (n = 6 independent samples) f TUNEL-stained tumor slices (scale bar: 2.5 mm). Tumor tissues collected from different groups at 24 h after various treatments. Experiments were performed one time. Source data are provided as a Source data file.

Fig. 4. Immune responses after treatment to TRAMP-C1 tumor-bearing mice.

Flow cytometric analysis images (a) and the statistical data (b) for in vivo DC maturation. Cells in the tumor-draining lymph nodes were collected after various treatments for the assessment by flow cytometry after staining with CD11c, CD80, and CD86. **p = 0.0044. Representative flow cytometric analysis images showing CD8⁺ T cells (CD3⁺ CD4^- CD8⁺) from different groups of mice. Proportions of tumor infiltrating CD8⁺ killer T cells in the tumor (up line) and draining lymph nodes (down line) (c) and the statistical data in the tumor (d) (**p = 0.0013) and in lymph node (e) among all cancer cells (*p = 0.0491) (n = 6 independent samples). The percentage values in the graphs were defined in relation to T cell populations. Data are shown as means ± s.d. two-tailed paired t-test. Source data are provided as a Source data file.