Exciting progress in ferroptosis-based nanomedicine for bladder cancer

Bladder cancer remains a major health concern worldwide, ranking as the fourth leading cause of cancer in men and surpassing 600,000 new cases yearly. Despite advances in chemotherapy and immunotherapy, a significant proportion of patients with bladder cancer experience poor responses to treatment. The problem lies in the ability of cancer cells to develop resistance to conventional therapies, which primarily work by inducing a specific type of cell death called apoptosis. When tumors become resistant to this mechanism, treatment options become limited and prognosis worsens.

One exciting new avenue in cancer research is ferroptosis, a distinct form of programmed cell death that is heavily dependent on iron. While ferroptosis offers a compelling way to overcome treatment resistance, harnessing its full potential in patients has proven challenging. Existing ferroptosis-inducing drugs have several limitations, including inefficient delivery to tumor sites, lack of precise targeting, and the dependence on external physical activators like heat or lasers, which are difficult to apply to internal organs. These limitations have prevented this powerful biological mechanism from becoming a first-line treatment option in bladder cancer.  

Against this backdrop, a research team from Sun Yat-Sen University, China, has developed an innovative solution that could overcome these issues. Their study, published in the journal Research on June 17, 2025, presents a novel nanomedicine that can not only deliver ferroptosis-inducing drugs directly to cancer cells but also help in the fight through other remarkable ways.

The researchers engineered their nanomedicine, named Fe-EGCG@RSL3, by combining iron (Fe²⁺) ions with epigallocatechin gallate (EGCG), a natural compound found in green tea, and encapsulating a potent ferroptosis-inducing chemical called RSL3. When mixed under the right conditions, these compounds self-assemble into the desired Fe-EGCG@RSL3 nanoparticles, which essentially act as a molecular delivery system. Once inside the tumor, the acidic environment causes the Fe-EGCG shell to break apart and release its cargo, increasing the intracellular ferrous concentration and thereby triggering ferroptosis.

After extensive experimentation in both cell cultures and mouse models, the team found that Fe-EGCG@RSL3 not only killed bladder cancer cells that were resistant to other treatments but also reprogrammed the tumor immune microenvironment. Using single-cell analysis, the researchers observed that their nanomedicine encouraged nearby beneficial immune cells to mature and become more active while reducing the presence of immune cells that typically suppress the anti-tumor response. This double effect of directly inducing cell death and boosting the immune system at tumor sites proved key to Fe-EGCG@RSL3's performance. “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,” highlights lead author Chengjunyu Zhang. Notably, the observed immunomodulation could be harnessed to make standard immunotherapy treatments work better.

Another advantage of the proposed Fe-EGCG@RSL3 system is that it does not require external activation and can be administered either through the bloodstream or directly into the bladder. “Our nanomedicine can effectively accumulate in tumor tissues after administration and spontaneously respond, overcoming the limitations of conventional physical response methods for deep pelvic organs,” explains Dr. Zhang. “Taken together, the findings of our study highlight avenues for potential nanomedicine-based cancer therapies through the secondary effects of ferroptosis induction.”

Safety testing showed that Fe-EGCG@RSL3 did not cause significant damage to healthy organs in mice, addressing yet another major concern with experimental cancer treatments. Moreover, the straightforward manufacturing process of Fe-EGCG@RSL3 means that it could be easily scaled up for clinical production. Although human trials will be necessary to ultimately confirm the treatment's effectiveness in patients, this study represents a significant step forward in developing new weapons against cases of resistant bladder cancer.

About the Journal

Launched in 2018, Research is the first journal in the Science Partner Journal (SPJ) program. Research is published by the American Association for the Advancement of Science (AAAS) in association with Science and Technology Review Publishing House. Research publishes fundamental research in the life and physical sciences as well as important findings or issues in engineering and applied science. The journal publishes original research articles, reviews, perspectives, and editorials. IF=10.7, Citescore=13.3

Sources: https://doi.org/10.34133/research.0735