A locally-adapted nanoreactor for autophagy inhibition-enhanced cascade starvation-chemodynamic therapy

Cutting off the energy supply of tumors and disrupting their redox homeostasis have emerged as two promising therapeutic strategies in oncology. However, a persistent challenge lies in overcoming tumor self-protection mechanisms while minimizing toxic side effects. To overcome this limitation, a locally-adapted nanoreactor (MCGH) is developed for autophagy inhibition-enhanced cascade starvation-chemodynamic therapy, which not only selectively enhances tumor treatment by inhibiting autophagy, but also minimizes damage to normal tissues through tissue-specific cascade catalytic reactions. Specifically, glucose oxidase (GOx)-loaded MCGH catalyzes intratumoral glucose conversion into hydrogen peroxide (H₂O₂), thereby simultaneously inducing starvation therapy while generating substrates for chemodynamic therapy (CDT). When exposed to the tumor microenvironment, the low pH and high levels of glutathione (GSH) trigger the degradation of MCGH to release Mn²⁺ ions. These ions subsequently catalyze Fenton-like reaction that transform H₂O₂ into highly toxic hydroxyl radicals (OH) for CDT. Additionally, concurrent autophagy inhibition by MCGH blocks OH clearance and prevents nutrient replenishment, thereby amplifying the therapeutic efficacy of this cascade strategy. Importantly, MCGH exhibits catalase (CAT)-like activity in normal tissues, effectively detoxifying H₂O₂ through its decomposition. By engineering a single material platform to execute different catalytic cascades, this work provides a new perspective for precision nanomedicine design.