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

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.