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

Insufficient concentrations of intracellular substrates such as hypoxia and H2O2 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-IrOx@PCM) was constructed via co-encapsulation of iridium oxide nanozyme (IrOx) and beta-lapachone (Lap) by using thermal-responsive phase-change materials (PCMs). After photothermal activation, the protective PCM layer was melted, causing the rapid release of IrOx and Lap. Simultaneously, the peroxidase-like nanozyme IrOx reacted with endogenous H2O2 to liberate highly toxic hydroxyl radicals (center dot OH) for inducing tumor cell death. Meanwhile, IrOx as another glutathione peroxidase nanozyme also consumed glutathione (GSH) to protect ROS from scavenging. Importantly, the released Lap efficiently generated H2O2 for facilitating the catalytic efficacy of IrOx 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.