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

ABSTRACT 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 BaTiO 3 (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. Yb 3+ /Er 3+ doping imparts intrinsic NIR‐II fluorescence, eliminating the need for external fluorophores or downconversion nanoparticles, while Mn 2+ 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 Mn 2+ ‐mediated H 2 O 2 decomposition to liberate molecular oxygen (O 2 ), 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.