Metal–Organic Framework (MOF)‐Based Ultrasound‐Responsive Dual‐Sonosensitizer Nanoplatform for Hypoxic Cancer Therapy

Abstract Sonodynamic therapy (SDT), which uses reactive oxygen species to target tumors, has shown promise in the management of unresectable cancers. However, the hypoxic tumor environment limits SDT efficiency, making complete tumor destruction challenging. Here, a dual‐sonosensitizer nanoplatform is developed by loading an alkyl radical generator (2,2‐azobis[2‐(2‐imidazolin‐2‐yl)propane] dihydrochloride, AIPH) onto a zirconium metal–organic framework (Zr‐MOF). The Zr‐MOF@AIPH nanoparticles (NPs) can produce singlet oxygen, which can kill tumor cells under normoxic conditions, as well as alkyl radicals, which can kill tumor cells under both normoxic and hypoxic conditions. The combination of these free radicals further enhances SDT efficiency. Meanwhile, the nitrogen generated owing to AIPH decomposition can reduce the cavitation threshold and enhance the acoustic cavitation effect, thereby promoting NP penetration at the tumor site. Moreover, Zr‐MOF@AIPH NPs exhibit good photoacoustic, fluorescence, and ultrasound imaging abilities due to their porphyrin‐based structure and the nitrogen generated, which can remotely control NP delivery and determine the optimal therapeutic time window, ensuring the maximization of SDT efficiency. In vitro and in vivo examinations prove the superior antitumor efficacy, excellent biocompatibility, and favorable imaging ability of Zr‐MOF@AIPH. This study spearheads the charge toward improving SDT efficacy in hypoxic environments via a combination of complementary sonosensitizers.