Chemodynamic therapy (CDT), employing Fenton or Fenton-like catalysts to convert hydrogen peroxide (H2O2) into toxic hydroxyl radicals (˙OH) to kill cancer cells, holds high promise in tumor therapy due to its high selectivity. However, the anticancer efficacy is unsatisfactory owing to the limited concentration of endogenous H2O2. Herein, thermal responsive nanoparticles with H2O2 self-sufficiency are fabricated by utilizing organic phase change materials (PCMs) to encapsulate iron-gallic acid nanoparticles (Fe-GA) and ultra-small CaO2. PCMs, acting as the gatekeeper, could be melted down by the hyperthermia effect of Fe-GA under laser irradiation with a burst release of Fe-GA and CaO2. The acidic tumor microenvironment would further trigger CaO2 to generate a large amount of H2O2 and Ca2+. The self-supplied H2O2 would be converted into ˙OH by participating in the Fenton reaction with Fe-GA. Meanwhile, in situ generation of Ca2+ could cause mitochondrial damage and lead to apoptosis of tumor cells. With efficient tumor accumulation illustrated in in vivo photoacoustic imaging, Fe-GA/CaO2@PCM demonstrated a superior in vivo tumor-suppressive effect without inducing systemic toxicity. The study presents a unique domino effect approach of PCM based nanoparticles with thermal responsiveness, H2O2 self-supply, and greatly enhanced CDT effects, showing bright prospects for highly efficient tumor treatment.
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