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Construction of multifunctional stimuli-responsive nanotherapeutics enabling improved intratumoral penetration of therapeutics and reversal of multiple-drug resistance(MDR)is potent to achieve effective cancer treatment.Herein,we report a general method to synthesize pH-dissociable calcium carbonate(CaCO3)hollow nanoparticles with amorphous CaCO3 as the template,gallic acid(GA)as the organic ligand,and ferrous ions as the metallic center via a one-pot coordination reaction.The obtained GA-Fe@CaCO3 exhibits high loading efficiencies to both oxidized cisplatin prodrug and doxorubicin,yielding drug loaded GA-Fe@CaCO3 nanotherapeutics featured in pH-responsive size shrinkage,drug release,and Fenton catalytic activity.Compared to non-responsive GA-Fe@silica nanopartides prepared with silica nanoparticles as the template,such GA-Fe@CaCO3 confers significantly improved intratumoral penetration capacity.Moreover,both types of drug-loaded GA-Fe@CaCO3 nanotherapeutics exhibit synergistic therapeutic efficacies to corresponding MDR cancer cells because of the GA-Fe mediated intracellular oxidative stress amplification that could reduce the efflux of engulfed drugs by impairing the mitochondrial-mediated production of adenosine triphosphate(ATP).As a result,it is found that the doxorubicin loaded GA-Fe@CaCO3 exhibits superior therapeutic effect towards doxorubicin-resistant 4T1 breast tumors via combined chemodynamic and chemo-therapies.This work highlights the preparation of pH-dissociable CaCO3-based nanotherapeutics to enable effective tumor penetration for enhanced treatment of drug-resistant tumors.