NIR-II Fluorescent Nanoplatforms with Defect-Regulated Piezoelectricity for Dual NIR-II/MRI-Guided, Hypoxia-Resilient Piezo-Chemodynamic Therapy and cGAS-STING Activation in Orthotopic Liver Tumor.

The development of multifunctional theranostic nanoplatforms with second near-infrared (NIR-II) fluorescence and magnetic resonance imaging (MRI), which enable deep-tissue imaging, hypoxia-tolerant ROS generation via on-demand, rapid piezodynamic therapy (PZDT) and sustained tumor-microenvironment-activated chemodynamic therapy (CDT), together with robust immunomodulation, remains a critical challenge in tumor therapy. Here, one-pot solvothermal synthesis of Mn, Yb, and Er co-doped BaTiO3 (FMBTO) is reported, a first-in-class NIR-II fluorescence-emitting piezoelectric nanocomposite that integrates imaging, catalytic therapy, and innate immune activation within a single framework. Yb3+/Er3+ doping imparts intrinsic NIR-II fluorescence, eliminating the need for external fluorophores or downconversion nanoparticles, while Mn2+ incorporation enables piezoelectric enhancement, T1-weighted MRI contrast, Fenton-like chemodynamic catalysis, and potent cGAS-STING immune activation. Defect engineering within the BTO lattice significantly enhances piezocatalytic reactive oxygen species (ROS) generation, even under severe hypoxia, and simultaneously promotes Mn2+-mediated H2O2 decomposition to liberate molecular oxygen (O2), thereby reversing hypoxia and downregulating HIF-1α. In an orthotopic liver tumor model, FMBTO demonstrates strong tumor accumulation, NIR-II/MRI-guided treatment precision, and ultrasound (US)-triggered PZDT-CDT synergy, leading to extensive tumor apoptosis, immune-cell recruitment, and robust STING pathway activation. Collectively, FMBTO establishes a versatile nanotheranostic paradigm that couples deep-tissue imaging with oxygen-independent ROS production and innate immune stimulation, offering a powerful strategy for treating hypoxic and immunosuppressed solid tumors.