Tumor Microenvironment-Mediated Activation of Oxidative Stress Storm for MRI-Guided Ferroptosis Therapy

Introduction: Ferroptosis therapy, despite its promise, encounters challenges such as compromised catalytic performance due to an inadequate H2O2 substrate, the robust antioxidant defense system within the tumor microenvironment (TME), and potential off-target adverse events, leading to suboptimal efficacy. Methods: To overcome these limitations, we propose a strategy for TME-mediated activation of a potent oxidative stress storm to enhance MRI-guided multiple-amplified ferroptosis therapy for tumors. Results: The synthesized Fe-LAP@HMON-TAM-PEOz nanoparticles demonstrate precise and highly effective tumor-specific catalysis for antitumor therapy. This is achieved through an improved tumor accumulation strategy driven by charge-reversal-mediated active targeting and a multiple amplification approach for ferroptosis therapy, involving H2O2 self-supplementation, GSH depletion, subsequent oxidative stress storm generation, and LPO accumulation, resulting in a robust antitumor response. Furthermore, the rapid degradation of nanoparticles in response to the H+/GSH stimulus within the TME facilitates the release of Mn2+ from Fe-LAP@HMON-TAM-PEOz. This released Mn2+ significantly enhances tumor brightness in T1-weighted MRI, characterized by a high r1 value. Conclusion: Consequently, our synthesized Fe-LAP@HMON-TAM-PEOz nanoparticles exhibit excellent biodegradability and minimal side effects, highlighting their tremendous potential for highly efficient tumor theranostics.