Cascade-Responsive Zwitterionic Polyprodrugs Leverage Fast Transcytosis for Deep Tumor Penetration and Intracellular Drug Release

The clinical translation of anticancer nanomedicines is significantly hindered by their inability to efficiently navigate the entire physiological CAPIR barriers (Circulation, Accumulation, Penetration, Internalization, and Release). To address this issue, we construct intelligent zwitterionic polyprodrugs, P(OC7A-DOX), which self-assemble into micelles. The design integrates cascade tumor-specific responses: (1) a hydrophilic shell of hypoxia-responsive poly(2-( N -oxide-hexamethyleneimino) ethyl methacrylate) (POC7A) that undergoes charge reversal in the tumor hypoxic and acidic microenvironment, and (2) a hydrophobic core containing doxorubicin (DOX) conjugated via a glutathione (GSH)-cleavable disulfide bond. Our study reveals that this system successfully orchestrates a spatial-temporal performance shift across the CAPIR cascade requirements. Importantly, the micelles maintain prolonged circulation due to the stealthy POC7A corona. Upon accumulation in hypoxic and acidic tumors, the POC7A segments are reduced and protonated, switching the surface property to a positively charged one, which dramatically enhances tumor tissue penetration and facilitates rapid cellular internalization via a transcytosis-like mechanism. Subsequently, the high intracellular GSH concentration triggers release of free DOX. In 4T1 tumor-bearing mice, they achieve significant tumor growth suppression with markedly reduced systemic toxicity compared to free DOX. This work provides an integrated nanoplatform that overcomes the key physiological barriers efficiently as a clinically promising nanomedicine.