Phase-change cascaded nanomedicine for intensive photothermal-enhanced nanocatalytic therapy via tumor oxidative stress amplification

Insufficient concentrations of intracellular substrates such as hypoxia and H 2 O 2 considerably reduce the effectiveness of reactive oxygen species (ROS)-associated cancer therapy. Modulating the tumor microenvironment (TME) for augmenting efficacy has become a promising strategy. Herein, a phase-change cascaded nanomedicine (Lap-IrO x @PCM) was constructed via co-encapsulation of iridium oxide nanozyme (IrO x ) and β-lapachone (Lap) by using thermal-responsive phase-change materials (PCMs). After photothermal activation, the protective PCM layer was melted, causing the rapid release of IrO x and Lap. Simultaneously, the peroxidase-like nanozyme IrO x reacted with endogenous H 2 O 2 to liberate highly toxic hydroxyl radicals (•OH) for inducing tumor cell death. Meanwhile, IrO x as another glutathione peroxidase nanozyme also consumed glutathione (GSH) to protect ROS from scavenging. Importantly, the released Lap efficiently generated H 2 O 2 for facilitating the catalytic efficacy of IrO x and provoke the cleavage of heat shock protein 90 (Hsp90) for overcoming tumor heat tolerance in photothermal therapy (PTT). As systematically demonstrated both in vitro and in vivo , this well-defined system achieved a superior antitumor effect via mild photothermal-enhanced nanocatalytic therapy. Our findings have provided the proof of concept of the phase change-mediated, in vivo catalytic activity of nanozymes that can be customized for intensive, TME-mediated, self-enhanced nanocatalytic cancer therapy.