Metal-polyphenol-network coated CaCO₃ as pH-responsive nanocarriers to enable effective intratumoral penetration and reversal of multidrug resistance for augmented cancer treatments

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 nanoparticles 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.