PEGylated Manganese–Zinc Ferrite Nanocrystals Combined with Intratumoral Implantation of Micromagnets Enabled Synergetic Prostate Cancer Therapy via Ferroptotic and Immunogenic Cell Death

Abstract

Therapeutic efficacy for prostate cancer is highly restricted by insufficient drug accumulation and the resistance to apoptosis and immunogenic cell death (ICD). Although enhanced permeability and retention (EPR) effect of magnetic nanomaterials could benefit from external magnetic field, it falls off rapidly with increased distance from magnet surface. Considering the deep location of prostate in pelvis, the improvement of EPR effect by external magnetic field is limited. In addition, apoptosis resistance and cGAS‐STING pathway inhibition‐related immunotherapy resistance are major obstacles to conventional therapy. Herein, the magnetic PEGylated manganese‐zinc ferrite nanocrystals (PMZFNs) are designed. Instead of providing external magnet, micromagnets into tumor tissues are intratumorally implanted to actively attract and retain intravenously‐injected PMZFNs. As a result, PMZFNs accumulate in prostate cancer with high efficacy, depending on the established internal magnetic field, which subsequently elicit potent ferroptosis and the activation of cGAS‐STING pathway. Ferroptosis not only directly suppresses prostate cancer but also triggers burst release of cancer‐associated antigens and consequently initiates ICD against prostate cancer, where activated cGAS‐STING pathway further amplifies the efficacy of ICD by generating interferon‐β. Collectively, the intratumorally implanted micromagnets confer a durable EPR effect of PMZFNs, which eventually achieve the synergetic tumoricidal efficacy with negligible systemic toxicity.

The crosstalk between ferroptosis and anti‐tumor immunity in the tumor microenvironment: molecular mechanisms and therapeutic controversy

“…Furthermore, recent studies, particularly those focused on nanoparticle‐based approaches, have provided ample evidence for the immunomodulatory effects of inducing ferroptosis in cancer cells. For example, many studies have demonstrated that ferroptotic cancer cells promote immune cell infiltration or activation, thereby improving the immunosuppressive TME [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 62 , 79 , 84 , 85 , 118 , 119 , 120 , 121 , 122 ]. Several studies have also shown that inducing ferroptosis in cancer cells significantly enhances the efficacy of immunotherapy [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ].…”

“…Recent studies have suggested the potential of integrating ferroptosis‐targeted therapy with immunotherapy for tumor treatment [ 46 , 47 ]. Several studies have indicated a cooperative effect between ferroptosis induction and ICIs [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ], suggesting a promising future for this combined treatment approach. However, further investigation has shown that ferroptosis has a complex impact on anti‐tumor immunity, affecting the feasibility of such a combination strategy.…”

Ferroptosis and ferroptosis-inducing nanomedicine as a promising weapon in combination therapy of prostate cancer

“…Zhang et al constructed magnetic PEGylated manganese-zinc ferrite nanocrystals. 114 By effectively inducing ferroptosis in prostate cancer cells and activating tumor immunogenic cell death by releasing antigens from ferroptotic cells, which in turn stimulate the cGAS-STING pathway, the nanocrystals achieved successful synergistic therapy of CRPC (Fig. 3D) (Fig.…”

Cubic Zinc-Doped Iron Oxide Nanoparticles with Poly(Ethylene Glycol) or Sodium Citrate Surface Coatings for Tumor Imaging

“…35 Wang et al demonstrated that PEGylated ferrites nanocrystals displayed a prolonged blood half-life time (6.8 h) compared to naked nanocrystals (2.7 h). 36 Therefore, a PEG-modified nanostructure may show a better diagnostic performance for tumors in the peripheral. Of note, the prolonged blood half-life time results in the decrease of MRI contrast agent in liver and hinders the rapid detection of hepatoma and liver metastases, which contain much less active Kupffer cells and blood vessels to normal liver tissue.…”

“…PEG can form a steric hindrance around the magnetic core to exclude the protein corona . Wang et al demonstrated that PEGylated ferrites nanocrystals displayed a prolonged blood half-life time (6.8 h) compared to naked nanocrystals (2.7 h) . Therefore, a PEG-modified nanostructure may show a better diagnostic performance for tumors in the peripheral.…”