Spermine Oxidase-DOX Conjugates Reshape Tumor Microenvironment via Carbonyl Stress to Potentiate Bladder Cancer Chemotherapy

The tumor's antioxidant defenses restrict the efficacy of standard therapies, resulting in compromised treatment responses and systemic tolerance. Conventional redox-disrupting strategies, designed to generate reactive oxygen species (ROS), are limited by both their reliance on single generation methods and the rapid clearance. Herein, we report an innovative strategy that employs spermine oxidase (SMOX) to catalyze the production of endogenous and highly cytotoxic acrolein, thereby creating a destructive carbonyl stress microenvironment to potentiate antineoplastic drug’s efficacy. As an example, SMOX and doxorubicin (DOX) were conjugated and co-encapsulated within mesoporous silica nanoparticles to form an integrated delivery platform (PMD). Notably, in vitro and in vivo results demonstrated that PMD sensitizes bladder and subcutaneous tumor cells to DOX by locally inducing carbonyl stress and oxidative damage, allowing for a reduced dosage of the chemotherapeutic agent. The underlying mechanisms involved enhanced ACR-mediated mitochondrial dysfunction and lipid peroxidation, P53 upregulation via GAPDH binding to induce apoptosis, and inhibition of the Warburg effect via suppression of glycolytic enzymes and Ras. Importantly, the therapeutic efficacy is achieved either local instillation or systemic administration, highlighting the translational promise of this platform for bladder cancer and other malignancies. To overcome tumor redox defenses, an integrated SMOX/DOX nanoplatform is developed. It promotes the in-situ production of highly cytotoxic acrolein via remodeling polyamine metabolism, inducing local carbonyl stress to potentiate chemotherapy and reduce required drug dosage, offering a novel strategy for treating bladder cancer and other malignancies. • SMOX/DOX nanoplatform potently disrupts the redox homeostasis of TME. • PMD triggers in-situ acrolein production via remodeling polyamine metabolism. • PMD-induced carbonyl stress potentiates chemo, offering a novel cancer therapy.