Glucose-hijacked nanobots: Enabling deep tumor penetration via a self-enhanced permeability cascade

The therapeutic efficacy of nanomedicine is critically hampered by poor tumor penetration. While nanomotors offer a promising approach to enhance delivery, their effectiveness is constrained by the limited and heterogeneous distribution of conventional fuels like H₂O₂. Here, we report glucose-hijacked nanobots TiMOF@Au@MnCaMOF-HA (denoted as TAMH) that exploit endogenous glucose as a self-filling fuel for enhanced mobility. After administration, the TAMH nanobots can improve tumor penetration and navigate to deeper tumor regions via a "moving-anchoring-loosening" triple-stage delivery strategy. In the acidic tumor microenvironment, TAMH can partially degrade to release Mn²⁺/Ca²⁺ ions and expose Au nanoparticles, initiating a catalytic cascade: Au nanoparticles hijack glucose to produce H₂O₂, which is subsequently catalyzed by Mn²⁺ ions into O₂ bubbles for enhanced mobility. Simultaneously, hyaluronic acid surface modification enables active anchoring to CD44-overexpressing 4 T1 breast cancer cells, while released Ca²⁺ ions enhance membrane permeability of nanobots by loosening the phospholipid packing. Importantly, treatment-triggered glucose uptake by stressed tumor cells creates a self-fueling cycle that sustains nanobot mobility and amplifies the treatment efficacy. This self-reinforcing mechanism enables a highly efficient synergistic combination of microwave thermal and dynamic therapies, achieving potent tumor ablation through localized hyperthermia, cytotoxic reactive oxygen species generation, as validated both in vitro and in vivo. This work establishes a paradigm of using endogenous metabolites for autonomous motion, advancing nanomaterials for precise cancer therapy.