Nanoplatform-mediated dual-strategy cholesterol depletion for potentiating tumor chemodynamic-immunotherapy

Regulating cholesterol metabolism presents a promising multi-pronged strategy in cancer therapy, targeting its roles in tumor growth, immune suppression, and treatment resistance. To overcome the limitations of single-target approaches, a novel nanoplatform was engineered. This system utilizes hyaluronic acid-coated mesoporous polydopamine to co-deliver a dual-metabolic modulator: simvastatin (a synthesis inhibitor, Sim) and cholesterol oxidase (Chox), alongside Mn 2+ ions. The platform orchestrates a coordinated attack: Simvastatin blocks de novo cholesterol synthesis, while Chox depletes existing membrane cholesterol. This depletion disrupts oncogenic signaling and reverses immunosuppression. Furthermore, the enzymatic reaction of Chox generates H 2 O 2 , which Mn 2+ ions convert into highly cytotoxic hydroxyl radicals via Fenton-like reactions, initiating self-amplifying chemodynamic therapy. The mesoporous polydopamine (mPDA) core ensures high cargo loading and stability and enables spatiotemporal coordination of these actions. The hyaluronic acid (HA) shell promotes active cluster of differentiation 44 (CD44)-targeting and enzyme-triggered payload release within the tumor. This paradigm-shifting approach not only disrupts cholesterol-driven oncogenesis but also leverages its metabolic byproducts to fuel a synergistic anti-tumor cascade, offering a powerful strategy for tumor-selective metabolic reprogramming and immunotherapy.