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 H 2 O 2 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 H 2 O 2 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 Mn 2+ from Fe-LAP@HMON-TAM-PEOz. This released Mn 2+ significantly enhances tumor brightness in T 1 -weighted MRI, characterized by a high r 1 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.