Cascade Ultrasonic Cavitation Enables Microbubble–Nanoparticle Hybrid to Broadly Accumulate and Penetrate into Pancreatic Ductal Adenocarcinoma

To address the challenges of limited drug accumulation and penetration in pancreatic ductal adenocarcinoma (PDAC), a cascade ultrasonic cavitation strategy designed to enhance drug delivery by sequentially overcoming biological barriers is developed. This approach employs a macrophage membrane‐modified microbubble–nanoparticle hybrid (MMB@TFHPD) capable of cascade ultrasonic cavitation. MMB@TFHPD consists of a microbubble coating (MMB) and a mesoporous silica core (TFHPD), coloaded with doxorubicin and perfluoropentane. Following intravenous administration, MMB@TFHPD accumulates near tumor endothelial cells via ligand–receptor interaction. Low‐intensity ultrasound (first US) is then applied to induce the primary ultrasonic cavitation, disrupting blood‐tumor barrier and enhancing TFHPD NPs accumulate within the tumor periphery. Upon exposure to the acidic tumor microenvironment (TME), the surface tannic acid–iron complexes (TA/Fe 3+ ) of TFHPD NPs degrade, exposing the mesoporous silica structure. High‐intensity US (second US) is subsequently applied, triggering liquid‐to‐gas phase transition of PFP and PFP microbubbles destruction, which induces extracellular matrix collapse, rapid drug release, and deep penetration into the tumor parenchyma. This process results in potent antitumor effects in PDAC therapy. In summary, this study introduces a promising cascade ultrasonic cavitation strategy to overcome key barriers in drug delivery for PDAC and other solid tumors.