A Multifunctional Fe-EGCG@RSL3 Nanomedicine Synergizes Ferroptosis Induction and Tumor Microenvironment Remodeling for Enhanced Bladder Cancer Immunotherapy.

Ferroptosis has promising potential for augmenting antitumor effects, but monotherapy with ferroptosis inducers in vivo has been reported to have limited efficacy in tumor management. The development of synergistic strategies with targeted capabilities is crucial for enhancing the antitumor efficacy of ferroptosis inducers. In this study, we designed and characterized a novel self-assembled nanomedicine by mixing ferrous ions (Fe(2+)) and epigallocatechin gallate (EGCG) in a controllable manner and encapsulating the ferroptosis inducer RSL3, named Fe-EGCG@RSL3. This multifunctional nanomedicine effectively induces ferroptosis and growth inhibition in bladder cancer cells and patient-derived organoids. In vivo, Fe-EGCG@RSL3 was enriched in the subcutaneous tumors of allogenic and xenograft mouse models, thereby substantially overcoming RSL3 resistance. Intravesical instillation of Fe-EGCG@RSL3 controls orthotopic bladder tumor progression. Furthermore, nanomedicine potentiates the therapeutic effect of anti-programmed cell death protein 1 (PD1) immunotherapy by increasing the cytotoxicity of CD8(+) T cells to cancer cells and modulating the proportions of both T-cell and myeloid cell subpopulations within the tumor immune microenvironment. Overall, Fe-EGCG@RSL3 has dual functions as a multifaceted nanomedicine that integrates ferroptosis induction with immunomodulation, offering a novel and clinically translatable strategy for bladder cancer therapy.