A Multifunctional Nanoplatform Based on Lactate Depletion and Hydrogen Peroxide Accumulation for MRI-Guided Tumor Therapy

The tumor microenvironment (TME) exhibits metabolic dysfunction characterized by lactate (LA) accumulation, which leads to tumor progression, angiogenesis, and therapy resistance. Targeting LA metabolism through lactate oxidase (LOX) converting LA to pyruvate and hydrogen peroxide (H2O2) under aerobic conditions is a promising therapeutic strategy. However, LOX activity is limited by TME hypoxia. To overcome this limitation, we developed an integrated nanotheranostic system based on hollow MnO2 nanoparticles loaded with LOX and cinnamaldehyde (CA) and modified with hyaluronic acid (HA) for tumor-targeted delivery (denoted as MCLH). In the acidic TME, MCLH decomposes to release LOX and CA, while MnO2 reacts with endogenous H2O2 to generate O2. The resulting O2 maintains LOX-mediated LA oxidation, thereby providing additional H2O2 to promote further O2 production, establishing a self-sustaining cycle that continuously consumes lactate. Meanwhile, CA depletes glutathione via Michael addition, disrupting redox homeostasis and enhancing H2O2 accumulation to increase oxidative stress. The released manganese ions (Mn2+) also enable magnetic resonance imaging (MRI) contrast for real-time monitoring. These cascading effects collectively achieve the synergistic regulation of LA metabolism and oxidative damage, providing an effective strategy for tumor treatment.