Dual-Responsive Polyprodrug Nanoparticles with Cascade-Enhanced Magnetic Resonance Signals for Deep-Penetration Drug Release in Tumor Therapy. Hao Qiubo,Wang Zhixiong,Zhao Wei,Wen Liewei,Wang Wenhui,Lu Siyu,Xing Da,Zhan Meixiao,Hu Xianglong ACS applied materials & interfaces Smart transformable nanocarriers are promising to treat deep-seated diseases but require adaptable diagnostic/imaging potency to reflect the morphology change and therapeutic feedback, yet their design and synthesis remains challenging. Herein, stimuli-responsive polyprodrug nanoparticles (SPNs) are formulated from the co-assembly of negatively charged corona and positively charged polyprodrug cores, exhibiting high loading content of camptothecin (CPT, ∼28.6 wt %) tethered via disulfide linkages in the core. SPNs are sequentially sensitive to tumor acidic condition and elevated reductive milieu in the cytosol for deep-penetration drug delivery. Upon accumulation at acidic tumor sites, SPNs dissociate to release smaller positively charged polyprodrug nanoparticles, which efficiently enter deep-seated tumor cells to trigger high-dosage parent CPT release in the reductive cytosolic milieu. Meanwhile, the polyprodrug cores of SPNs labeled with DTPA(Gd), a magnetic resonance imaging contrast agent, can trace the cascade degradation and biodistribution of SPNs as well as the resulting intracellular CPT release. The longitudinal relaxivity of SPNs increases stepwise in the above two processes. The size-switchable polyprodrug nanoparticles exhibit remarkable tumor penetration and noteworthy tumor inhibition and , which are promising for endogenously activated precision diagnostics and therapy. 10.1021/acsami.0c16110