In order to prevent the aggregation of ICG and enhance its stability, a novel nanoplatform (TiO2:Yb,Ho,F-β-CD@ICG/HA) was designed for NIR-induced phototherapy along with multi-mode imaging(UCL/MRI/Flu). In this nanosysytem: TiO2:Yb,Ho,F was used as upconversion materials and applied in vivo for the first time; β-CD acted as a "protective umbrella" to load separated ICG and avoid the low phototherapy efficiency because of its aggregation; HA was the capping agent of β-CD to prevent ICG unexpected leaking and a target to recognize CD44 receptor. The nanosystem exhibited excellent size (~200 nm) and photo- and thermal-stability, preferable reactive oxygen yield and temperature response (50.4 °C) under 808 nm laser. It could efficiently target and suppress tumor growth. The imaging ability (UCL/MRI) of TiO2:Yb,Ho,F could facilitate diagnosis of the tumor, especially for deep tissues. Altogether, our work successfully improved the phototherapy efficacy through incorporating the ICG into the cavity of β-CD and applied TiO2:Yb,Ho,F for upconversion imaging in vivo.