Tumor Microenvironment‐Activated Nanosystem With High Aggregation and On‐Demand Degradation for Imaging‐Guided Synergistic Hydrogenothermal Therapy

Abstract Photothermal therapy (PTT) as an emerging antitumor approach has many advantages. However, when the PTT generates localized hyperthermia to induce cell apoptosis, excess reactive oxygen species (ROS) and inflammatory cytokine release will threaten the peritumoral healthy tissues, thus it is challenging to develop efficient strategies to reduce the undesirable PTT‐mediated side effects. Herein, the authors report exploitation of hypoxia‐responsive degradation in designing a synergistic hydrogenothermal therapeutic nanosystem for ROS elimination and anti‐inflammatory action to enhance antitumor activity. The nanosystem (MA@NHC) is successfully constructed by encapsulating melanin‐nanoparticles (MNPs) and amine‐borane (AB) inside functionalized hyaluronic acid to obtain MA@NH, then capped with 4T1 cell‐membranes. Synergistic integration of the homotypic aggregation with EPR effect can improve the tumor‐targeting properties of MA@NHC. Upon specifically targeting tumor, sequentially time‐dependent MNPs and AB release can be triggered by hypoxia tumor‐microenvironment. Based on the superior NIR light‐absorption ability, widely permeated MNPs are activated for photoacoustic imaging‐guided PTT. Meanwhile, the high intra‐tumor acidity accelerates the production of H 2 via AB to scavenge excess ROS and reduce PTT‐induced inflammatory responses, which can be further sped up during PTT. Remarkably, as an antioxidant and anti‐inflammatory agent, the MNPs synergize with H 2 to protect peritumoral normal cells from damage.