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oai:figshare.com:article/34027379 2026-09-29T19:05:27Z category_4 category_7 category_12 category_13 category_14 category_19 category_64 category_132 category_133 portal_63 item_type_6 month_year_09_2026

Bifunctional Nanozymes for Synergistic Treatment by Boosting Oxidative Stress and Regulating the Protein Kinase B Pathway Qi Fang (199280) Xiaojun Zhang (178074) Chong-Bo Ma (2195002) Quanyi Liu (11502591) Jingyuan Yu (15197077) Jiaqi Li (220961) Hao Sun (14095) Jicheng Ma (25138640) Hui Wei (126971) Yan Du (229593) Biochemistry Medicine Cell Biology Genetics Molecular Biology Pharmacology Cancer Infectious Diseases Plant Biology weaken antioxidant defenses responsive catalytic conversion reactive oxygen species protein kinase b minimizing adverse effects functionalized formulation ap endogenous hydrogen peroxide boosting oxidative stress boosting chemotherapeutic efficacy pod )- like suppresses tumor growth molecule akt inhibitors conventional akt inhibitors 2 </ sub like activities synergistic treatment sequencing analysis safer alternative related signaling precise inhibition muc1 aptamer largely driven generalizable approach enhance chemosensitivity bifunctional nanozymes although small akt phosphorylation adr models aberrant activation Chemoresistance and dose-limiting toxicity remain major challenges in cancer chemotherapy, largely driven by aberrant activation of the protein kinase B (AKT) survival pathway. Although small-molecule AKT inhibitors can enhance chemosensitivity, their systemic activity frequently disrupts normal metabolic processes and causes severe side effects. Here, we report an “all-in-one” catalytic nanodrug that integrates a dual-enzyme-mimicking nanozyme (GPMM) with doxorubicin (Dox) to overcome these limitations. GPMM simultaneously exhibits peroxidase (POD)-like and phosphatase-like activities, enabling two synergistic biochemical actions: (i) amplification of reactive oxygen species (ROS) through tumor-microenvironment-responsive catalytic conversion of endogenous hydrogen peroxide (H₂O₂), and (ii) depletion of intracellular nicotinamide adenine dinucleotide (NADH) to weaken antioxidant defenses. This dual modulation induces persistent oxidative stress and leads to precise inhibition of AKT phosphorylation, functioning as an effective and safer alternative to conventional AKT inhibitors. As a result, Dox@GPMM markedly enhances chemosensitivity and suppresses tumor growth in nonresistant MCF-7 breast cancer models, while the MUC1 aptamer-functionalized formulation AP-Dox@GPMM effectively reverses Dox resistance in MCF-7-ADR models, without observable systemic toxicity. RNA-sequencing analysis further reveals that the nanozyme regulates key genes involved in metabolism, survival, and AKT-related signaling, thereby reshaping cellular response to chemotherapy. Collectively, this nanozyme-driven redox strategy provides a robust and generalizable approach for boosting chemotherapeutic efficacy while minimizing adverse effects, offering strong translational potential for overcoming resistance across diverse tumor types. 2026-09-29T00:00:00Z Text Journal contribution 10.1021/acsnano.6c12630.s001 https://figshare.com/articles/journal_contribution/Bifunctional_Nanozymes_for_Synergistic_Treatment_by_Boosting_Oxidative_Stress_and_Regulating_the_Protein_Kinase_B_Pathway/34027379 CC BY-NC 4.0