Self-amplifying ROS nanorobot with orthogonal NIR activation for enhanced photodynamic-chemodynamic combination therapy.

While combination therapies generally exhibit superior therapeutic outcomes compared to single-modality treatments, current photodynamic-chemodynamic (PDT/CDT) combination strategies remain limited by two major factors: (i) the restricted tissue penetration depth of light and (ii) the insufficient endogenous hydrogen peroxide (H2O2) concentration within the tumor microenvironment (TME), both of which compromise therapeutic efficacy. To overcome these obstacles, we developed an innovative hybrid nanorobot (EcN + UCNPs@mSiO2-MnO2-ZnPc) that integrates engineered Escherichia coli Nissle 1917 (EcN) with orthogonally emissive upconversion nanoparticles (C@3S). Specifically, MnO2 decomposes into Mn2+ under acidic TME conditions, subsequently catalyzing the conversion of H2O2 into cytotoxic hydroxyl radicals (˙OH) and oxygen, which exhibits dual effects of tumor cell eradication and hypoxia alleviation. Meanwhile, C@3S transforms 980 nm laser radiation into blue-violet emission, activating the EcN that preferentially colonizes tumor regions and overexpresses respiratory chain enzyme II (NDH-II), thereby replenishing H2O2in situ and sustaining chemodynamic therapy (CDT). Additionally, zinc phthalocyanine (ZnPc) is excited by the 808 nm-converted red emission to generate singlet oxygen (1O2), further enhancing reactive oxygen species (ROS) accumulation and amplifying oxidative stress in tumor cells. Collectively, our findings demonstrate significant tumor growth inhibition through this self-amplifying ROS-generation mechanism. This multifunctional hybrid nanorobot offers a promising platform for precision cancer therapy with spatiotemporal controllability.