Endogenous Fe^(2+)-activated ROS nanoamplifier for esterase-responsive and photoacoustic imaging-monitored therapeutic improvement

Chemodynamic therapy(CDT)is well acknowledged as potent reactive oxygen species(ROS)-mediated anticancer strategy.Especially,the study about labile iron pool(LIP)as endogenous ferrous catalyzer has paved the way for future CDT development.However,limited H_(2)O_(2) expression,mild acidity,reduced glutathione(GSH)ablation of ROS,etc.,all require employing alternate peroxo-complex to achieve enhanced CDT effect.As a non-Fenton-type substrate,artesunate(ART)has been utilized as a source of free radicals through decomposition of endoperoxide bridges catalyzed by ferrous ions,nonetheless,the non-tumor-specific delivery,inferior pharmacokinetics,and hydrophobic nature minimize the efficacy of ART in physiological systems.Herein,we devise a PPA nanoamplifier by conjugating ART with PEG-functionalized Pd@Pt nanoplates(PP NPs)to form ester linkage,ensuring specific intratumoral esterase-responsive ART release.Significantly,the PPA nanoamplifier combines the in situ decomposition of ARTs endoperoxide bridges by Fe^(2+) to superoxide anions(O_(2)^(·-))and peroxidase(POD)-like enzymatic catalysis of endogenous H_(2)O_(2) by PP to hydroxyl radicals(*OH),thus achieving amplified ROS-mediated tumor therapy.Besides,PPA displays GSH destruction potential,thereby protecting ROS from the cleavage by GSH oxidation.In addition,the strong absorption of PPA in near-infrared(NIR)region also endows PPA with photoacoustic property to realize imaging-guided CDT.In short,by taking advantages of the high enrichment and esterase-responsive drug release at tumor sites,PPA amplified ROS signals via dual pathways,killing tumor cells in vitro are inhibiting tumor growth in vivo,thereby realizing high-efficiency non-Fenton CDT.We believe our novel anti-tumor strategy based on PPA will broaden the future of ROS-mediated tumor-targeted therapy.