Endogenous Amplification of Apoptosis via p53 Regulation using a Cascade Nanocatalytic Medicine

ABSTRACT Nanocatalytic therapy is an emerging strategy that leverages in situ catalytic reactions within the tumor microenvironment to convert endogenous substrates into cytotoxic species, achieving spatially confined cancer cell killing with reduced systemic toxicity. However, the lack of durable, DNA‐focused cytotoxic mechanisms hampers the translational efficacy of nanocatalytic therapy. Herein, we proposed a cascade nanocatalysis‐mediated strategy for endogenous amplification of apoptosis, achieved by an engineered metal organic framework nanomedicine (MOF‐Au‐L‐Arginine, abbreviated as MAL). The MOF serves both as a nanocatalyst and as a carrier for L‐Arginine (L‐Arg), while embedded Au nanoparticles enhance nanocatalyst reactivity. Subsequently, MOF catalyzes the generation of hydroxyl radicals (•OH) and superoxide anions (O ₂ ^•− ), and then the O ₂ ^•− undergo a cascade reaction with NO released from L‐Arg, generating highly cytotoxic peroxynitrite (ONOO–), which has greater cytotoxicity to tumor cells, can induce extensive DNA damage, and simultaneously impair DNA repair and disrupt the cell cycle. Genome‐wide RNA sequencing reveals MAL can activate the p53 pathway, thereby regulating apoptosis related proteins. In addition, MAL reduces mitochondrial membrane potential and promotes mitochondrial‐mediated apoptosis through the BAX/Bcl‐2/caspase‐3 axis, further amplifying endogenous apoptosis in tumor cells. In vivo, MAL effectively inhibits tumor growth with favorable biocompatibility.