Sonodynamic
therapy (SDT) holds growing promise in deep-seated or large solid
tumor treatment owing to its high tissue penetration depth ability; however, its therapeutic efficacy is often compromised due to the hypopermeable and hypoxic characteristics in the
tumor milieu. Herein, a semiconducting
polymer nanoparticle (SPNC) that synergistically enhances
tumor penetration and alleviates tumor hypoxia is reported for sonodynamic
therapy of large solid
tumors. SPNC comprises a semiconducting
polymer nanoparticle core as a sonodynamic converter coated with a poly (
ethylene glycol) corona. An
oxygen-modulating
enzyme,
catalase, is efficiently conjugated to the surface of nanoparticles via the coupling reaction. Superior to its counterpart SPNCs (SPNC2 (84 nm) and SPNC3 (134 nm)), SPNC with the smallest size (SPNC1 (35 nm)) can efficiently penetrate throughout the
tumor interstitium to alleviate whole tumor hypoxia in a large solid
tumor model. Upon ultrasound (US) irradiation, SPNC1 can remotely generate sufficient
singlet oxygen to eradicate
tumor cells at a deep-tissue depth. Such a single treatment of SPNC1-medicated sonodynamic
therapy effectively inhibits
tumor growth in a large solid
tumor mouse model. Therefore, this study provides a generalized strategy to synergistically overcome both poor penetration and
hypoxia of large
tumors for enhanced
cancer treatment.