Nanoparticle-mediated synergistic disruption of tumor innervation and redox homeostasis for potent antineoplastic therapy

Innervation is closely linked to several biological processes that promote tumor growth, making it an increasingly promising therapeutic target. In this study, biomimetic hollow MnO₂ nanocarriers camouflaged with tumor cell membranes (HMLC) are developed to encapsulate lidocaine, an innervation inhibitor, for effective antineoplastic therapy. This approach aims to suppress nerve fiber growth and induce intracellular redox imbalance. Benefiting from the tumor-homing effect, HMLC accumulates in cancerous tissue during circulation and is endocytosed by tumor cells through homologous membrane fusion. Once inside the cells, MnO₂ can be degraded by the overproduced glutathione and H₂O₂, leading to the tumor-specific release of Mn²⁺ and lidocaine. The Mn²⁺-mediated Fenton-like reaction promotes the accumulation of reactive oxygen species, and the resulting oxidative stress, combined with glutathione depletion, exacerbates redox imbalance. Simultaneously, the released lidocaine downregulates nerve growth factor and neuronatin. The reduction in nerve growth factor significantly inhibits nerve fiber formation and infiltration in tumor tissue, while the decrease in neuronatin reduces intracellular Ca²⁺, which helps prevent metastasis. Overall, this strategy highlights the potential of nanoparticle-based tumor innervation disruptors in antineoplastic therapy.