Manganese-mineralized boric acid-modified bovine serum albumin loaded on metal-organic frameworks as a pH- and GSH-responsive nanozyme for active targeted drug delivery.

Nanozyme-driven chemotherapy kinetics therapy (CDT), in combination with traditional chemotherapy, is an effective approach to overcome the poor efficacy of a single chemotherapy drug in long-term treatment settings due to drug resistance. We developed a manganese-loaded boronic acid-functionalized bovine serum albumin, and loaded it onto Zeolitic imidazolate framework-8 (ZIF-8) to obtain a nanozyme PBM@ZIF-8 with excellent drug-loading capacity. The nanozyme PBM@ZIF-8 showed notable glutathione peroxidase-like and peroxidase-like activities, with high loading capacity of 10.34% with doxorubicin (DOX) and achieved pH- and glutathione (GSH)-responsive release, which is approximately three times the drug release amount in physiological conditions. Subsequently, DOX loaded PBM@ZIF-8 (PBM@ZIF-8-DOX) achieved active targeting of Hepatocellular carcinoma (HCC) by specifically binding to sialic acid receptors, accumulating extensively within HCC cells. Through catalytic reduction of intracellular GSH levels and increased reactive oxygen species levels, this nanozyme effectively kill HepG2 cells when combined with DOX chemotherapy. Additionally, we constructed an 3D HCC microsphere model to further validate the high targeting efficiency and HCC killing efficacy of the nanoparticles in vitro. In conclusion, PBM@ZIF-8 serves as an effective drug delivery platform, providing a promising strategy for multimodal treatment of HCC.